1,3-aminoalcohols

ABSTRACT

Novel 1,3-aminoalcohol of the formula   WHEREIN N HAS THE VALUE OF 1 TO 4, INCLUSIVE, WHEREIN R&#39;&#39;, R&#39;&#39;&#39;&#39;, and R&#39;&#39;&#39;&#39;&#39;&#39; are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, inclusive, and alkoxy of 1 to 6 carbon atoms, inclusive, or CF3, are prepared. The new compounds of formula IV per se as well as in the form of acid addition salts have diuretic activity and some of them have antihyperglycemic activity. Compounds of formula IV are thus useful to provide diuretics in mammals and are also useful as oral antidiabetic agents.

United States Patent" Primary Examiner-Alton D. Rollins Attorney-Hans L.Berneis and John Kekich Szmuszkovicz [451 June 6, 1972 [5411,3-AMINQALCOHOLS I [72] Inventor: Jacob Szmuszkoviez, Kalamazoo, Mich.[57] ABSTRACT [73] Assignee: The Upjohn Company, Kalamazoo, Mich.la'ammoalcohol oflhe formula [22] Filed: Oct. 30, 1970 v (CH: R 4 [2!]Appl. No.: 85,718 E Related U.S. Applicatlon'Data l [62] Division ofSer. No. 556,892, June 13, 1966, Pat. No. N 3,558,599, which is adivision of Ser. No. 786,385,

Dec. 23, 1968, Pat. No. 3,595,867.

, [52] U.S.Cl.. ..260/239 B, 260/239 BF, 424/244 Int. Cl. ..C07d whereinn has h value of l to 4 inclusive wherein R1 n 0 Search B and R; are y gg alkyl of l to 6 carbon atoms I inclusive, and alkoxy of l to 6 carbonatoms, inclusive, or CF:,, [56] Reerences cued are prepared. The newcompounds-of formula W per se as UNITED STATES PATENTS well as in theform of acid addition salts have diuretic activity and some of them haveantihyperglycemic activity. Com- 3,257,413 6/1966 ShOft ..260/294.7 undof f ula IV are thus useful to provide diuretics in mammals and are alsouseful as oral antidiabetic agents.

10 Claims, No Drawings 1,3-AMINOALCOHOLS CROSS-REFERENCES TO RELATEDAPPLICATIONS This application is a division of application Ser. No.

556,892 filed June 13, 1966, now US. Pat. No. 3,558,599 and 5 representshexamethyleneimino, wherein R is an alkyl containing from 1 to 6 carbonatoms, inclusive, wherein R, R, R are selected from the group ofsubstituents consisting of hydrogen, halogen, alkyl and alkoxycontaining from 1 to 6 carbon atoms, inclusive, and--CF and wherein Acis the acyl radical of a hydrocarbon carboxylic acid containing from 2to 12 carbon atoms, inclusive.

The invention further includes the compounds of formulae IV, [Va and IVbwhen in the form of the N-oxides, acid addition salts and quaternaryalkyl ammonium halides in which the alkyl group has from 1 to 12 carbonatoms, inclusive, and the halogen can be chlorine, bromine and iodine.Also the acid addition salts of the compounds of formula III areembraced by this invention.

Examples of the cycloalkyl radical illustratively represented by theformula are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Examples of the heterocyclic amino radical having from 5 to 10 nuclearatoms, include: pyrrolidino, 2-

methylpyrrolidino, 2-ethylpyrrolidino, 2,2-dimethylpyrrolidino,3,4-dimethylpyrrolidino, 2-isopropylpyrrolidino, 2-sec.butylpyrrolidino, and like alkylpyrrolidino groups, morpholino,2-ethylmorpholino, 2-ethyl-5-methylmorpholino,

LII

3,3-dimethylmorpholino, thiamorpholino, 3- methylthiamorpholino,2,3,6-trimethylthiamorpholino, 4- methylpiperazino, 4-butylpiperazino,piperidino, 2-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino,4-propylpiperidino, 2-pr0pylpiperidino, 4-isopropylpiperidino, and likealkylpiperidino groups, hexarnethyleneimino, 2-methylhexamethyleneimino,3,-dimethylhexamethyleneimino, homomorpholino, 1,2,3,4-tetrahydroquinolyl, heptamethyleneimino, octamethyleneimino,3-azabicyclo[3,2,2 ]nonan-3-yl, 2-azabicyclo-[2,2,2]octan-2-yl, and thelike.

Illustrative examples of alkyl groups having from 1 to 6 carbon atomsare methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,pentyl, Z-methylbutyl, neopentyl, hexyl, 2- methylpentyl, 3-methylpentyland the like. Alkyl groups for the quaternary ammonium halide saltsinclude, in addition to the preceding alkyl groups, others such asheptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The halogenmoiety in such salts includes iodine, bromine and chlorine.

Illustrative examples of the acyl groups Ac of hydrocarbon carboxylicacids are particularly the acyl groups of alkanoic acids of 2 to 12carbon atoms, e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, hexanoyl, octanoyl, decanoyl, ,B-cyclopentylpropionyl,lauroyl; of benzoic and aralkanoic acids, e.g., benzoyl, phenylacetyl,3-phenylpropionyl, toluoyl, ethylbenzoyl, propylbenzoyl; of alkenoicacids, e.g., acryloyl, crotonoyl, chrysanthemummonocarbonyl, cinnamoyl,hexenoyl; of alkynoic acids, e.g., propioloyl, 2- and 3-butynoyl and thelike.

Under halogen substitutents for R, R or R is understood fluorine,chlorine, bromine and iodine.

The novel compounds III, IV, Wu and IVb exist in different steroisomericforms such as geometric and optically active forms (e.g., compounds offormula III have at least two asymmetric carbon atoms, while the finalproducts, IV, IVa and IVb, have at least three asymmetric carbon atoms)as well as in racemic mixtures. These optically active forms and racemicmixtures and geometric isomers are also encompassed by this invention.

The process of the present invention comprises: heating a diketocompound of formula I in which one of the radicals on the centralcarbonyl group is a 2-oxocycloalkyl group having from 5 to 8 carbonatoms, inclusive, and the other group is substituted or unsubstitutedphenyl, with a heterocyclic amine having from 5 to 10 nuclear atoms,inclusive, in the presence of an acidic catalyst, e.g.,p-toluenesulfonic acid, to give the unsaturated keto compound of formulaII; hydrogenating the thus-obtained compound II in the presence of ahydrogenation catalyst, preferably a noble metal catalyst such asplatinum oxide, rhodium, palladium or the like to add stepwise one andthereupon two molar equivalents of hydrogen, thus yielding respectively(with 1 molar equivalent of hydrogen) the keto compound III and (with 2molar equivalents of hydrogen) the alcohol IV. The thus-obtainedl,3-amino alcohols IV can be converted to alcohol derivatives such asethers (IVa) with an alkyl halide (l to 6 carbon atoms) in the presenceof a base, or with a lower alkanol (1 to 6 carbon atoms) in the presenceof anhydrous hydrogen chloride, and to esters (IVb) with an acidanhydride or acid halide in a suitable organic solvent.

The amino function in formulae lV, lVa and IVb compounds furthermorepennits the transformation of these compounds, by neutralization withinorganic and organic acids, into acid addition salts such as thehydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,perchlorate, pamoate, cyclohexanesulfamate, methanesulfonate,ethanesulfonate, ptoluenesulfonate, benzenesulfonate, tartrate, citrate,lactate, and the like. By treatment of the compounds of formulae IV, Naand IVb with peracids such as m-chloroperbenzoic acid, peracetic acid,perbenzoic acid, perphthalic acid, and the like, the correspondingN-oxide derivatives are obtained. By treatment of the compounds offormulae 1V, IVa and IVb with alkyl halides, the correspondingquaternary ammonium halide salts are obtained.

The compounds of formulae IV, IVa and lVb, including the acid additionsalts, the N-oxides, and the alkyl quaternary ammonium halides thereof,are compounds of significant diuretic activity. They may be administeredto mammals and birds by both oral and parenteral routes in order toproduce their pharmacological, that is, diuretic effects. For oraladministration, the new compounds of formulae IV, IVa and IVb, as wellas the acid addition salts, the N-oxides and the quaternary ammoniumhalide salts, can be compounded into solid and liquid unit dosage formssuch as tablets, capsules, powders, granules, syrups, elixirs and thelike, containing the appropriate amounts for treatment. For tablets,common pharmaceutically acceptable carriers are used such as starch,lactose, kaolin, dicalcium phosphate and the like. The compounds IV, IVaand lVb can also be given as powders, particularly in gelatin capsuleswith or without carriers such as methylcellulose, magnesium stearate,calcium stearate, talc and the like. For fluid preparations, thesecompounds may be dissolved or suspended in aqueous alcoholic vehicleswith or without buffering agents and flavoring mixtures.

The thus-obtained pharmaceutical formulations are administered toedematous animals for the treatment of conditions associated with excesselectrolyte retention and excess fluid retention. For example, thecompositions are useful in treating the following conditions: edemaassociated with hepatic disease, edema and toxemia of pregnancy,hypertensive vascular disease, premenstrual fluid retention andcongestive heart failure. Dosages between 0.5 and 30 mg./kg. of bodyweight are suitable to produce significantly increased diuresis. Forexample, the ether cis-l-[2-(a,p-dimethoxybenzyl)cyclohexyl]-piperidineof melting point 83-85 C. produced at 5 mg. dosage level per kg. of bodyweight ofrats a 73 percent increase in diuresis, as determined by theprocedure of Lipschitz et al., J. Pharmacol Exp. Therap. 79, 97, 1943.

The compounds of Examples 38, 39, 48, 54, 55, 97, 99, 100 and 136A havedemonstrated significant anti-hyperglycemic activity in rats. They areuseful as oral antidiabetic agents.

As noted above, the new compounds of formulae IV, IVa and IVb can beused in the form of their acid addition salts with inorganic or organicacids, for example, hydrochlorides, lactates, sulfates, tartrates,hydroiodides, hydrobromides, and the like. Moreover, the fluosilicatesof these compounds are useful moth-proofing agents according to U. S.Pat. Nos. 1,915,334 and 2,075,359. The thiocyanic acid addition salts ofthe same compounds can be condensed with formaldehyde to form resinouspolymers which according to U. S. Pat. Nos. 2,425,320 and 2,606,155 areuseful as pickling inhibitors. The trichloroacetic acid addition saltsof the compounds of the same formulae IV, IVa and IV]; are useful asherbicides, for example, against Johnson grass, yellow foxtail, greenfoxtail, Bermuda grass and quack grass.

The alkyl quaternary ammonium halides of the compounds of formulae IV,[Va and Nb, such asa-(3,4,5-trimethoxyphenyl)-2-(hexahydro-l-methyl-l-azepinium)cyclohexanemethanoliodide (Example 142), possess high wetting power and electroconductivityand are thus suitable to prepare electrocardiographic jellies.

A suitable composition of an electrocardiographic jelly thus preparedcomprises:

Parts Glycerol 5 Starch l0 Quaternary ammonium salt 60 Water 100 Thejelly is prepared by mixing the starch, glycerol and water and thenadding the quaternary ammonium salt. The mixture is then allowed tostand for at least two days with occasional agitation to allow theformation ofa gel.

The starting materials of formula I are known in part from the art,e.g., Campbell et al., J. Am. Chem. Soc. 82, 2389, (1960); Linn et al.,J. Am. Chem. Soc. 78, 6066 (1956);

Eistert et al., Ann. 650, 133 (1961). An elegant method by which the1,3-diones of the type of formula I are synthesized consists of thereaction of a selected cycloalkanone with pyrrolidine or piperidine togive the corresponding enamine and to react the enamine with a selectedsubstituted or unsubstituted benzoyl chloride [Campbell et al., J. Org.Chem. 28, 379 (1963)]. This particular method is shown repeatedly in theExamples in order to synthesize hitherto unknown 1,3- diones of the typeof formula I.

In carrying out the process of the present invention a 1,3- diketocompound (I) is reacted with heterocyclic amine in the presence of aacid catalyst and preferably under conditions in which the waterproduced in the condensation process is separated from the reactionmixture such as by employing an azeotropic separator together with thereflux condenser. As solvent, essentially water-free organic solventsare used such as benzene, toluene, xylene or the like. The heterocyclicamines used include particularly pyrrolidine, 2-methylpyrrolidine,2-ethylpyrrolidine, 2,2-dimethylpyrrolidine, 3,4- dimethylpyrrolidine,2-isopropylpyrrolidine, 2-sec.butylpyrrolidine and other likealkylpyrrolidines; morpholine, 2-ethylmorpholine,2-ethyl-5-methylmorpholine, 3,3-dimethylmorpholine, thiamorpholine,3-methylthiamorpholine, 2,3,6- trimethylthiamorpholine and other likealkylmorpholines and alkylthiamorpholines; 4-methylpiperazine,4-butylpiperazine and other like alkylpiperazines; piperidine,Z-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine,4-propylpiperidine, 2-propylpiperidine, 4-isopropylpiperidine and otherlike alkylpiperidines; hexamethyleneimine, Z-methylhexamethyleneimine,3,6-dimethylhexamethyleneimine and other like alkylhexamethyleneimines;homomorpholine, l,2,3,4-tetrahydroquinoline, heptamethyleneimine,octamethyleneimine, 3-azabicyclo-[3.2.2]nonane,2-azabicyclo[2.2.2]octane,'and the like.

The reaction is generally carried out at temperatures between 50-l50 C.but lower or higher temperatures are operative. Preferably, the reactionis carried out at the reflux temperature of the reaction mixture. Thetime for completion of the reaction is between 1 hour and 48 hours, butif low temperatures are used, longer reaction times are necessary. Whenthe reaction is terminated, the product is isolated in conventionalmanner such as evaporating the reaction mixture to dryness.

The keto product of formula II is then hydrogenated in the presence of acatalyst, preferably platinum oxide, at a hydrogen pressure between 40and 60 pounds per square inch. Larger or smaller pressures can be used,but pressure between 50-55 pounds at the beginning of the reaction arefound to be most convenient. The reaction can be followed by thehydrogen absorption and can be allowed to go to completion, that is, tothe point of addition of 2 molar equivalents of "hydrogen to give thealcohol of formula IV, or alternatively may be interrupted after theaddition of 1 molar equivalent of hydrogen to give the keto compound offormula III. In cases where the addition of hydrogen is slow, additionalamounts of catalyst may be added after an interval of several hours.Other catalysts that can be used in this reaction are palladium andrhodium, and these catalysts can be used with catalyst carriers such ascharcoal, alumina and the like. After the hydrogenation is completed,the product is isolated by filtering the mix- ,ture to remove thecatalyst and evaporating the solvent to obtain either the keto compoundof formula III or the alcohol of formula IV. The thus-isolated productsare purified by conventional means such as by crystallization andrecrystallization, chromatography, or the like. If desired, the ketoproduct of formula III can be hydrogenated again to give the alcohol offormula IV.

The conversion of the alcohol of formula IV to an ether of formula IVais usually achieved by two methods: (I) reacting the alcohol of formulaIV in liquid ammonia containing sodium amide or potassium amide at lowtemperature with the selected alkyl halide, or (2) reacting the alcoholof formula IV with a lower alkanol in the presence of hydrogen chloride.The starting temperature of the first method is usually the temperatureof a Dry Ice-acetone bath, that is, approximately --70 C. and'iscompleted at about room temperature. In the preferred embodiment of thisinvention, the selected alcohol (IV), is dissolved in ether and is addedto liquid ammonia containing sodium amide under continuous stirring.When this mixture reaches the Dry Ice-acetone bath temperature, asolution of thealkyl halide, preferably an alkyl iodide, is added over afew minutes time to allow cooling. When the calculated amount of alkylhalide is consumed, the reaction mixture in the flask is removed fromthe Dry Ice-acetone bath and allowed to warm to room temperature undercontinuous stirring. Instead of sodium amide, other strong basiccompounds can be used such as potassium amide, lithium amide, and thelike. Instead of liquid ammonia and alkali metal amides, other reactionsystems can be used, e.g., butyl lithium in the presence oftetrahydrofuran and a temperature range of about 70 to 25C. After thereactionis terminated, the ether thus produced (lVa) is isolated byconventional procedures such as extraction, evaporation of solvents,formation of amine addition salts such as the hydrochloride, and usingthe differential water solubility of the hydrochloride and the like. Forpurification, recrystallization andchromatography are usually employed.v

In the second method, the alcohol IV is stirred with a solution ofhydrogen chloride gas in a lower alkanol, e.g.,

methanol, ethanol, propanol, l-butanol, 2-butanol and the like, usuallyat room temperature. Lower or higher temperatures are operative,however. The product is obtained as a hydrochloride of the amino ether.The free base is obtained by treating the hydrochloride witha base,e.g., 20 percent aqueous sodium hydroxide, extracting the free base witha waterimmiscible solvent, e.g., ether, methylene chloride, chloroformand the like and evaporating the solvent.

Esters (IVb) of the alcohol of formula IV are usually ob- I tained inconventional manner, that is, treatment of the alcohol with an acidanhydride or acid halide, preferably in solution at room temperature.The solvents used in this reaction are methylene chloride,tetrahydrofuran, pyridine and the like. The anhydrides used in thisreaction are usually of hydrocarbon carboxylic acids, e.g., of alkanoicacids such as acetic, propionic,-butyric, isobutyric, valeric, hexanoic,heptanoic, octanoic acids and the like; of benzoic and aralkanoic acidssuch as benzoic acid, salicyclic acid, toluic acid, phenylacetic acid,3-phenylpropionic acid and the like; of cycloalkanoic acids, e.g., ofcyclohexanecarboxylic acid and the like. The acid halides used in thisreaction can be of alkanoic acids, particularly higher alkanoic acidshaving from 6 to 12 carbon atoms, such as hexanoyl chloride, heptanoylchloride, octanoyl chloride, decanoyl chloride, undecanoyl chloride,lauroyl chloride or the acid bromides thereof, but the chlorides andbromides of lower alkanoic acids are also useful. The invention alsoencompasses the use of the anhydrides and acid chlorides and bromides ofunsaturated acids such as cinnamic acid, acrylic acid, crotonic acidpropiolic acid, 2-butynoic acid, chrysanthemummonocarboxylic acid andthe like. After termination of the reaction, the product is isolated byconventional procedures such as extraction, chromatography,crystallization and the like.

Acid addition salts of the amino alcohols (IV), amino ethers (Na) andamino esters (IVb) are synthesized in the usual manner, that is, bydirectly reacting the acid with the free amine, preferably in an aqueousor anhydrous solvent such as water, ether, methanol, ethanol, ethylacetate or the like. Evaporation of the solvent provides the desiredacid addition salt.

N-oxidesof the compounds of formulae (IV), (Na) and (IVb) are obtainedby reacting the compound at a tempera ture between 0-30 C., preferablyat the start of the reaction at a temperature between 0l0 C., with aperacid such as peracetic, perpropionic, perbenzoic, 'perphtahlic,mchloroperbenzoic or other organic peracids in a solvent such asmethanol, ethanol, ether or the like. Evaporation of the solventprovides the desired N-oxide of the products of formulae IV, IVa andIVb.

The alkyl quaternary ammonium halides of products of formula IV, IVa andIVb are produced by conventional methods such as heating to reflux asolution of the selected compound IV, IVa or IVb in the presence ofmethanol, ethanol, acetonitrile or the like with a selected alkyl halidesuch as an iodide or bromide or, less desirably, a chloride of methyl,ethyl, propyl, butyl, isobutyl, isopropyl, pentyl, hexyl, heptyl, octyl,decyl, undecyl, dodecyl or isomers of these alkyl compounds. After thereaction is terminated, the reaction mixture is evaporated to dryness togive the product which can be purified by recrystallization from organicsolvents such as methanol, ethanol, ether, Skellysolve B hexanes,mixtures thereof and the like.

It is obvious from the configuration of products III, IV, [Va and IVbthat these products can exist in more than one isomeric structure, sincethe compounds of formula III have at least two asymmetric centers andthose of formula IV, Na and IVb have at least three asymmetric centers,-as noted above. It will be seen from the Examples that many of thereactions are either stereo-specific giving only one single product(racemic) or are stereo-selective, that is, giving one major componentwith smaller amounts of other components. Thus, the hydrogenation of thecompound II to the ketone III with platinum oxide appears to give onlyone single form of the cisketone. Heating the thus-obtained cis-ketonewith a base, for example, refluxing it with piperidine, produces asingle transketone (III), which according to thermodynamic principles ofstability has the substituents on the cycloalkane moiety in theequatorial position.

Further hydrogenation of a cis-k'etone of formula III with platinumoxide as catalyst produces one single cis-alcohol form (racemate A).Heating this cis-alcohol of formula IV with trifluoroacetic acidproduces another formula IV cis-alcohol (racemate B).

Further hydrogenation. of a trans-ketone of formula III with platinumoxide as catalyst produces one single formula IV trans-alcohol (racemateC) which can be converted to the other formula IV trans-alcohol(racemate D) with trifluoroacetic acid. Reduction of a trans-ketone offormula III with lithium aluminum hydride produces the twoabove-mentioned trans-alcohols of formula IV; The racemates can beresolved by standard methods. The subsequent Examples further illustratethe stereo-isomeric considerations.

The following Examples are illustrative of the process and the productsof the present invention, but are not to be construed as limiting.

EXAMPLE I 2-( 3,4,5 -Trimethoxybenzoyl )cyclohexanone A mixture of 147g. (1.5 moles) of cyclohexanone and 213.3 g. (3 moles) of pyrrolidinewas refluxed in 2,250 ml. of benzene in a flask equipped with anazeotropic separator. After the water formed during the reaction wascollected, the solution was evaporated to dryness in vacuo and theresulting crude oil, consisting of l-pyrrolidino-l-cyclohexene, was useddirectly for the next step.

A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g.; 0.6 mole) in240 ml. of chloroform was added during a period of 2 hours to a solutionof the crude l-pyrrolidino-1-cyc1ohexene in 630 ml. of chloroform, undera nitrogen atmosphere, with continuous stirring while keeping thetemperature between 5 to 10 C. After the solution was stirred overnight(about 18 hours) at room temperature (about 22 to 25 C.), there wasadded 900 ml. of 10 percent aqueous hydrochloric acid, and the resultingmixture was stirred at room temperature for 2 hours. The aqueous layerwas extracted with two 150 ml. portions of chloroform, and thechloroform extracts were combined with the chloroform layer above. Thecombined extracts were washed with water, saturated aqueous sodiumbicarbonate solution, water and saturated salt solution. Thethus-obtained chloroform solution was dried by passing it throughanhydrous sodium sulfate and the dry solution was evaporated to give aresidue which was crystallized Analysis:

Calcd. for C I-1 Found: C, 65.48; H, 6.84

EXAMPLE 2 2-(3,4,5-Trimethoxybenzoyl)cyclopentanone A mixture of 126 g.(1.5 moles) of cyclopentanone and 213.3 g. (3 moles) of pyrrolidine wasrefluxed in 2,250 ml. of benzene in a flask equipped with an azeotropicseparator. After the calculated amount of water, produced during thecondensation, had been collected, the reaction mixture was evaporated togive as an oil l-pyrrolidino-l-cyclopentene.

A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g.; 0.6 mole) inchloroform was added to a chloroform solution of the oilyl-pyrrolidino-l-cyclopentene over a period of 1 hour. The reactionmixture was thereupon worked up as in Example 1 to give a brown oilweighing 190 g. This oil was dissolved in 500 ml. of ethanol and theethanol solution was added to a solution of 172 g. of cupric acetatemonohydrate in 2,600 ml. of water. The mixture was stirred for one-halfhour, cooled and filtered, providing a crude copper complex of 2-(3,4,5-trimethoxybenzoyl) cyclopentanone. This product was crystallized frommethylene chloride to give 70 g. of the pure copper complex melting at206208 C.

Analysis:

Calcd. for C H CuO C, 58.29; H, 5.54; Cu, 10.28 Found: C, 58.58; H,5.81; Cu, 9.49

The thus-obtained copper complex (70 g.) was dissolved in 350 ml. ofchloroform and decomposed with 670 ml. of percent aqueous hydrochloricacid to give 60 g. (yield 36 percent) of2-(3,4,5-trimethoxybenzoyl)cyclopentanone having a melting point of 8186C. A sample of this material was recrystallized from Skellysolve Bhexanes to give 2-(3,4,5- trimethoxybenzoly)cyclopentanone of meltingpoint 9295 C.

Analysis:

Calcd. for C.,H...

Found: C,

In a run twice the size of the above synthesis, a yield of 47 percentwas obtained.

EXAMPLE 3 2-( 3 ,4,5-Trimethoxybenzoyl )cycloheptanone A mixture of 500g. of cycloheptanone (4.5 moles), 785 g. of morpholine (9 moles), 900ml. of toluene and 5 g. of ptoluenesulfonic acid was refluxed for 23hours, collecting the water produced in the reaction with an azeotropicseparator. Ninety-eight ml. of a lower phase was collected anddiscarded. The remaining mixture was then evaporated in vacuo to give anoil which was distilled. The fraction boiling between 1 l9-125 C.consisting essentially of 262.7 g. of lmorpholino-1-cycloheptene (32percent yield).

In the manner given in Example 1, 3,4,5-trimethoxybenzoyl chloride (92.5g.; 0.4 mole) was reacted with 181.37 g. (1 mole) ofl-morpholino-l-cycloheptene. The crude product was crystallized from 500ml. of methanol and gave a first crop of 26 g. of 2-(3,4,5-trimethoxybenzoyl)cycloheptanone of melting point 99-100 C.After two more recrystallizations from methanol, the product had amelting point of lO7-108 C.

Analysis:

Calcd. for C H O Found: From the above methanolic filtrate another 48.3g. of 2- (3,4,5-trimethoxybenzoyl)cycloheptanone was obtained as asecond crop. The total yield was 61 percent.

EXAMPLE 4 2-(p-Methoxybenzoyl)cyclohexanone A solution of 167 g. (0.98mole) of p-anisoyl chloride in 480 ml. of chloroform was added during aperiod of 1.5 hours to a solution of 371.7 g. (2.46 moles) of distilledl-pyrrolidino-lcyclohexene in 1260 ml. of chloroform. The temperaturewas kept between 5-10 C. by cooling with ice. After stirring for aperiod of about 20 hours at room temperature, the mixture was decomposedby addition of 1,800 ml. of 10 percent aqueous hydrochloric acid over aperiod of 20 minutes. The mixture was then stirred for 2 hours, allowedto settle, the organic layer was separated and the aqueous layerextracted twice with 250-ml. portions of chloroform. The originalorganic layer and the chloroform extracts were combined, washed withwater, saturated salt solution, and then dried by passage through sodiumsulfate and evaporated. The residue resulting from the above evaporationwas a brown oil which was dissolved in l l. of ethanol and added to asolution of 344 g. of cupric acetate monohydrate in 5,200 ml. of water,preheated to 65 C. The mixture was stirred for 0.5 hour, cooled to roomtemperature and filtered. The obtained precipitate was washed with waterand then with ether. It was then dissolved in 800 m1. of chloroform andadded to a solution of 300 ml. of concentrated hydrochloric acid in1,100 ml. of water. The mixture was stirred for 1 hour. The organiclayer was separated, and the aqueous layer was extracted once withchloroform. The combined chloroform original layer and extract werewashed with water, saturated salt solution, dried by passing throughanhydrous sodium sulfate and evaporated, to give a solid which wascrystallized from 7 l. of methanol, yielding 136.5 g. of2-(p-methoxybenzoyl)cyclohexanone having a melting point of 1 15-128 C.A second crop of 26 g., melting point 116-127 C., was obtained from themother liquor; the total yield was 71 percent. A recrystallized samplefrom methanol of 2-(p-methoxybenzoyl) cyclohexanone had a melting pointof l 17-l22 C.

Analysis:

Calcd. for c,,n,,o,;

Found:

EXAMPLE 5 2-(p-Methoxybenzoyl)cyclopentanone In the manner given inExample 2, 204 g. (1.2 moles) of panisoyl chloride was reacted withl-pyrrolidino-l-cyclopentene prepared from 252 g. (3 moles) ofcyclopentanone. The crude product was converted to the copper complex asin Example 4, the complex being crystallized from chloroformether togive g. of copper complex of 2-(p-methoxybenzoyl)cyclopentanone with amelting point of 252 C. (dec.). The copper complex was decomposed withhydrochloric acid to give 67 g. of an oil which was crystallized frommethanol to give 13.9 g. of 2-(p-methoxybenzoyl)cyclopentanone ofmelting point 82-83 C. The filtrate from the first crystallization wasevaporated to dryness and the residue crystallized fromether-Skellysolve B hexanes to give 30.1 g. of a second crop ofZ-(p-methoxybenzoyl)cyclopentanone of melting point 7677 C. (total yield17 percent). Two recrystallizations from methanol gave2-(p-methoxybenzoyl)cyclopentanone having a melting point of 83-87 C.

Analysis:

Calcd. for C I-I O Found:

2-(p-Ethoxybenzoyl)cyclohexanone In the manner given in Example 2,l-piperidino-l-cyclohex- EXAMPLE l42-[p-(Methylcarbamoyloxy)benzoyllcyclohexanone In the manner given inExample 2, l-piperidino-l-cyclohexene was reacted with p-ethoxybenzoylchloride in chloroform 5 ene was reacted withp-methylcarbamoyloxybenzoyl chloride solution to give, after the coppercomplex purification procedure (Example 2),2-(p-ethoxybenzoyl)cyclohexanone.

EXAMPLE 7 2-(p-Benzyloxybenzoyl)cyclohexanone In the manner given inExample 2, l-pyrrolidino-lcyclohexene 'wasreacted withp-benzyloxybenzoyl chloride in chloroform solution to give, after thecopper complex purification procedure (Example 2),2-(p-benzyloxybenzoyl)cyclohexanone of melting point I ll-l l 1.5 C.

EXAMPLE 8 EXAMPLE 9 2-(o-Methoxybenzoyl)cyclohexanone In the mannergiven in Example 2, l-piperidino-l-cyclohexene was reacted witho-methoxybenzoyl chloride in chloroform solution to give, after thecopper complex purification procedure (Example 2),2-(o-methoxybenzoyl)cyclohexanone of melting point 6568 C.

EXAMPLE 1O 2-(o-I-Iydroxybenzoyl)cyclohexanone In the manner given inExample 2, 1-piperidino-l-cyclohexene was reacted with o-acetoxybenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(0-acetoxybenzoyl)cyclohexanone.The thus-obtained 2-(o-acetoxybenzoyl)cyclohexanone was subjected toalkaline hydrolysis, the mixture acidified and the 2-(o-hydroxybenzoyl)cyclohexanone recovered by extraction.

EXAMPLE ll 2-( 2-Methoxy-4-methylbenzoyl)cyclohexanone In the mannergiven in Example 2, l-piperidino-l-cyclohexene was reacted with2-methoxy-4-methylbenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2), 2-(2-methoxy-4-methylbenzoyl)cyclohexanone.

EXAMPLE l2 2-(p-Methoxybenzoyl)-4,4-dirnethylcyclohexanone In the mannergiven in Example 2, l-piperidino4,4- dimethyl-l-cyclohexene was reactedwith p-methoxybenzoyl chloride in chloroform solution to give, after thecopper complex purification procedure (Example 2),2-(p-methoxybenzoyl)-4,4-dimethylcyclohexanone.

EXAMPLE l3 2-(3,5-Dimethyl-4-methoxybenzoyl)cyclohexanone In the mannergiven in Example 2, l-pyrrolidino-lcyclohexene was reacted with3,5-dimethyl-4-methoxybenzoyl chloride in chloroform solution to give,after the copper complex purification procedure (Example 2), 2-(3,5'dimethyl-4-methoxybenzoyl)cyclohexanone of melting point l-l26 C.

in chloroform solution to give, after the copper complex purificationprocedure (Example 2), 2-[p-(methylcarbamoyloxy)benzoyl]cyclohexanone.

EXAMPLE l5 2-( 3,4-Methylenedioxybenzoyl )cyclohexanone In the mannergiven in Example 2, l-piperidino-l-cyclohexene was reacted with3,4methylenedioxybenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2),2-(3,4-methylenedioxybenzoyl)cyclohexanone.

EXAMPLE l6 Z-(p-Trifluoromethylbenzoyl)cyclohexanone In the manner givenin Example 2, l-piperidino-l-cyclohex ene was reacted withp-trifiuoromethylbenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2),2-(p-trifluoromcthylbenzoyl)cyclohexanone.

EXAMPLE l7 2-( p-Chlorobenzoyl)cyclohexanone In the manner given inExample 2, l-piperidinol-cyclohexene was reacted with p-chlorobenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(p-chlorobenzoyl)cyclohexanone.

EXAMPLE l8 2-(p-I-Iydroxybenzoyl)cyclohexanone In the manner given inExample 2, l-piperidinol-cyclohexene was reacted with p-acetoxybenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(p-acetoxybenzoyl)cyclohexanone.The thus-obtained 2-(p-acetoxybenzoyl)cyclohexanone was subjected toalkaline hydrolysis, the mixture acidified and theZ-(p-hydroxybenzoyl)cyclohexanone recovered by extraction.

EXAMPLE l9 2-(o-Methylbenzoyl)cyclohexanone In the manner given inExample,2, l-piperidino-l-cyclohexene was reacted with o-methylbenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(o-methylbenzoyl)cyclohexanone.

EXAMPLE 20 2-(p-Methylbenzoyl)cyclohexanone In the manner given inExample 2, l-pyrrolidino-lcyclohexene was reacted with p-methylbenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (EXAMPLE 2), 2-(p-methylbenzoyl)cyclohexanone ofmelting point l08-l 10 C.

EXAMPLE 21 2-( 2,4-Dimethylbenzoyl )cyclohexanone In the manner given inExample 2, l-pyrrolidino-lcyclohexene was reacted with2,4-dimethylbenzoyl chloride in chloroform solution to give, after thecopper complex purification procedure (Example 2),2-(2,4dimethylbenzoyl)c yclohexanone of melting point 5 l-52.5 C.

EXAMPLE 22 2-( 2-Methoxy'4-methylbenzoyl)cyclohexanone In the mannergiven in Example 2, l-piperidino-l-cyclohexene was reacted with2-methoxy-4-methylbenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2),2-(2-methoxy-4-methylbenzoyl)cyclohexanone.

EXAMPLE 23 EXAMPLE 24 2-(p-Allyloxybenzoyl)cyclohexanone In the mannergiven in Example 2, l-piperidino-l-cyclohexene was reacted withp-allyloxybenzoyl chloride in chloroform solution to give after thecopper complex purification procedure (Example 2),2-(p-allyloxybenzoyl)cyclohexanone.

EXAMPLE 25 2-[p-(Carboxymethoxy)benzoyljcyclohexanone In the mannergiven in Example 2, l-piperidino-l-cyclohexene was reacted withp-(carboxymethoxy)benzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2),2-[p-(carboxymethoxy)benzoyl]cyclohexanone.

EXAMPLE 26 2-(p-Benzyloxybenzoyl)cycloheptanone In the manner given inExample 2, l-pyrrolidino-lcycloheptene was reacted withp-benzyloxybenzoyl chloride in chloroform solution to give after thecopper complex purification procedure (Example 2),2-(p-benzyloxybenzoyl)cycloheptanone.

EXAMPLE 27 2-(p-Ethoxybenzoyl)cyclooctanone In the manner given inExample 2, l-morpholino-l-cyclooctene was reacted with p-ethoxybenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(p-ethoxybenzoyl)cyclooctanone.

EXAMPLE 28 2-(2,3,4-Trimethoxybenzoyl)cyclooctanone In the manner givenin Example 2, l-piperidino-I-cyclooctene was reacted with2,3,4-trimethoxybenzoyl chloride in chloroform solution to give, afterthe copper complex purification procedure (Example 2),2-(2,3,4-trimethoxybenzoyl)cyclooctanone.

EXAMPLE 29 2-(p-Bromobenzoyl)cyclooctanone In the manner given inExample 2, l-piperidino-l-cyclooctene was reacted with p-bromobenzoylchloride in chloroform solution to give, after the copper complexpurification procedure (Example 2), 2-(p-bromobenzoyl)cyclooctanone.

EXAMPLE 30 to 10 nuclear atoms, inclusive, with a selected benzoylchloride. Representative starting materials, thus prepared, include:2-(3,5-diiodobenzoyl) cyclopentanone; 2-(pfluorobenzoyl)cyclohexanone;2-( 2-methoxy-4- chlorobenzoyl )cyclohexanone; 2-(2-methoxy-3-methylbenzoyl) cyclohexanone;2(2-methyl-4-trifluoromethylbenzoyl)cyclohexanone;2-(3,4-dipropylbenzoyl)cycloheptanone; 2-(2,5-dich1orobenzoyl)cycloheptanone; 2-(3,4- dichlorobenzoyl )cyclooctanone; 2-(p-propoxybenzoyl)cyclooctanone; 2-( 2,5-dii0dobenzoyl )cycloheptanone;2-(3-fluorobenzoyl)cyclopentanone; 2-(pbromobenzoyl)cyclopentanone;2-(p-hexylbenzoyl)cyclopentanone; 2-( 3-pentylbenzoyl )cyclohexanone;2-( 2-bu tylbenzoyl)cyclohexanone; 2-( 2-propylbenzoyl)cycloheptanone;2-( 3-ethylbenzoyl )cyclooctanone; 2-( 2-methoxy-5-bromo)cyclopentanone; 2benzoylcyclooctanone; 2-benzoylcycloheptanone;and the like.

EXAMPLE 31 3,4,5-Trimethoxyphenyl 2-piperidinol -cyclohexenl-yl ketone Amixture consisting of 35 g. (0.12 mole) of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone, 30.6 g. (0.36 mole) of piperidine, 960ml. of toluene, and 0.8 g. of p-toluenesulfonic acid was refluxed for 23hours under nitrogen using an azeotropic separator (during this time 1.8ml. of water was collected). The mixture was thereupon evaporated todryness to give partially crystalline 3,4,5-trimethoxyphenyl 2-piperidino- 1 -cyclohexen- 1 -yl ketone.

EXAMPLE 3 2 a-( 3 ,4,5-Trimethoxyphenyl)-2-piperidinocyclohexanemethanol and its hydrochloride A solution of3,4,5-trimethoxyphenyl 2-piperidino-1- cyclohexen-l-yl ketone preparedfrom 35 g. of 2-(3,4,5- trimethoxybenzoyl)cyclohexanone and 30.6 g. ofpiperidine, as in Example 31] in 300 ml. of ethanol was hydrogenated inthe presence of 1.2 g. of platinum oxide at an initial pressure of 50.1pounds of hydrogen. Two molar equivalents of hydrogen were taken upduring 3.5 hours. The mixture was filtered through a filter aid andevaporated to dryness. The oily residue was dissolved in 400 ml. ofether and 400 ml. of 10 percent aqueous hydrochloric acid was added. Thethus-obtained reaction mixture was stirred for 0.5 hour. A suspensionwas obtained which was filtered, yielding an original filtrate" and asolid which was washed with ether. The solid was twice recrystallizedfrom methanol to give 14.7 g. of a-(3,4,5-trimethoxyphenyl-Z-piperidinocyclohexanemethanol hydrochloride ofmelting point 265-266 C. An analytical sample, prepared by additionalrecrystallization from methanol had a melting point of 266267 C.Ultraviolet: sh 228 (8,100); sh 232; A max. 269 (825); sh 278 (612).

Analysis:

Calcd. for C H NOJ'ICI:

C, 63.06; H, 8.57; Cl, 8.87; N, 3.50 Found: C, 62.99; H, 8.24; Cl, 8.66;N, 3.46

The above original filtrate was separated into layers, the aqueous layerwas extracted with ether and then basified and extracted with methylenechloride. The extract was washed with water and saturated salt solution,then dried by pouring through anhydrous sodium sulfate and thewater-free solution was evaporated to give 5.0 g. of an oil. The oil wasconverted to the hydrochloride with ethereal hydrogen chloride to give asecond crop of 0.7 g. of a-(3,4,5-trimethoxyphenyl)-2-piperidinocyclohexanemethanol hydrochloride (total yield 32 percent;15.4 g.).

The ether layer, after washing, drying and evaporation, gave 6.1 g. ofan oil which was redissolved in ether and allowed to crystallize,yielding 0.5 g. of a-(3,4,5-trimethoxyphenyl)-2-hydroxycyclohexanemethanol of melting point -l31 C. (after additionalrecrystallization from ether).

Analysis:

Calcd. for c,,r-r,,o,=

Found: v c, 64.69; H, 8.29

EXAMPLE 33 3 ,4,5-Trimethoxyphenyl 2-morpholino- 1 -cyclohcxenl -ylEXAMPLE 34 a-( 3 ,4 ,5-Trimethoxyphenyl)-2-morpholinocyc1ohexanemethanol and its hydrochloride A solution of3,4,5-trimethoxyphenyl 2-morpholino-lcyclohexen-l-yl ketone [produced asin Example 33 from 8.75 g. of 2,-(3,4,5-trimethoxybenzoyl)cyclohexanone]in 100 ml. of ethanol was hydrogenated in the presence of 0.3 g. ofplatinum oxide catalyst at an initial hydrogen pressure of 52.5 pounds.Two molar equivalents of hydrogen were taken up during a period of 6ours. The mixture was filtered through diatomaceous earth (Filtercel)and evaporated to dryness. The resulting oil was dissolved in 100 ml. of10 percent aqueous hydrochloric acid, 100 ml. of ether was added and themixture was stirred for one-half hour. The aqueous layer was extractedtwice with two 50-ml. portions of ether. The ether extracts werecombined, washed with water, then with saturated salt solution, andfinally dried by passage through anhydrous sodium sulfate. Thethus-obtained solution was evaporated to give 2.3 g. of an oily materialwhich after crystallization from ether gave 1 g. of1-(3,4,5-trimethoxybenzoyl)-l-cyclohexene of melting point 73 74 C.

The above aqueous layer was cooled in ice, basified by adding sodiumhydroxide solution and extracted with methylene chloride (three portionsof 100 ml.). The extracts were combined, washed with water and saturatedsalt solution, and dried by passing through anhydrous sodium sulfate.The thusobtained solution was concentrated to give 7.89 g. of an oilymaterial which was converted to the hydrochloride by adding a solutionof hydrogen chloride in ether. The solid thus obtained wasrecrystallized frommethanol-ether to give 5 g. (42 percent yield) ofa-(3,4,5-trimethoxyphenyl)-2-morpholinocyclohexanemethanol hydrochlorideof melting point 20520 6 C.

Ultraviolet: sh 288 (8,150); sh 236 (6,350); A max. 269 (788); sh 278(555).

Analysis:

Calcd. for C ,,H ,NO -HCl:

C, 59.76; H, 8.03; Cl, 8.82; N, 3.49 Found: C, 59.81; H, 8.52; l, 8.52;N, 3.57

Example 35 2-( 4-methyll -piperazinyl)- 1- Example 36 a-( 3,4,5-Trimethoxyphenyl )-2-(4-methyll -piperazinyl)cyclohexanemethanoldihydrochloride A solution of 3,4,5-trimethoxyphenyl2-(4-methyl-lpiperazinyl)-l-cyclohexenl-yl ketone, prepared from 8.75 g.of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone as in Example 35, wasdissolved in ml. of methanol and then hydrogenated in the presence of0.3 g. of platinum oxide at an initial pressure of 54 pounds. After 6.5hours, the hydrogenation became sluggish, therefore, 0.03 mole of aceticacid and 0.3 g. of platinum oxide were added. After another period of 3hours a total of 2 molar equivalents of hydrogen was absorbed. Themixture was filtered through diatomaceous earth (Filtercel) andevaporated to dryness. The resulting oil was dissolved in 100 ml. of 10percent aqueous hydrochloric acid and 100 ml. of ether and the solutionwas stirred for 0.5 hour. The aqueous layer was extracted with threeSO-ml. portions of methylene chloride. The extracts were discarded. Theaqueous solution was then basified and extracted with four portions of50 ml. each of methylene chloride. The methylene chloride extracts werecombined, washed with water and with saturated salt solution, dried bypassing through anhydrous sodium sulfate and evaporated to give 5.9 g.of oil. This oil was dissolved in ether and then acidified with 35 ml.of 2N ethereal hydrogen chloride. The resulting solid was recrystallizedfrom methanol, yielding 4.4 g. (31 percent yield) of a-(3,4,5-trimethoxyphenyl )-2-(4-methyll -piperazinyl )cyclohexanemethanoldihydrochloride hemimethanol solvate of melting point 232-233 C.

Ultraviolet: sh 228 (8,400); sh 234.5 (6,850); A max. 270.5 (980); sh278 (915).

Analysis:

Calcd. for C ,l-l N,O;2HCl' /& cruou;

C, 55.24; H, 8.19; Cl, 15.17; Found: C, 54.90; H, 8.05; CI, 15.30;

Example 37 p-Methoxyphenyl 2-piperidinol -cyclohexen- 1 -yl ketone Inthe manner given in Example 31, 23.2 g. (0.1 mole) of 2-(p-methoxybenzoyl)cyclohexanone was heated with 25.5 g. (0.3 mole) ofpiperidine in 800 ml. of toluene in the presence of 0.67 g. ofp-toluenesulfonic acid to give p-methoxyphenyl2-piperidino-l-cyclohexen-1-y1 ketone.

Example 38 Cis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol Asolution of p-methoxyphenyl 2-piperidino-l-cyclohexenl-yl ketone(obtained from a synthesis of the same scale as shown in Example 37) in300 m1. of ethanol was hydrogenated in the presence of l g. of platinumoxide under an initial hydrogen pressure of 51 pounds. Two molarequivalents of hydrogen were absorbed during a period of 2.5 hours. Themixture was filtered through Filtercei diatomaceous earth. The filtratewas then evaporated to dryness and the residue dissolved in 250 ml. ofether. The ether solution upon standing produced crystals which wererecovered by filtration and washed with ether. One g. of material wasobtained having a melting point l52-l68 C. This material afterrecrystallization from methanol-ether was found to be thep-toluenesulfonic acid salt ofcis-A-a(p-methoxyphenyl)2-piperidinocyclohexanemethanol of melting pointl82l 83 C. Ultraviolet: A max. 223 (21,800); sh 256 (705); sh 262 (980);sh 268 1,360); 275 (1,530); 282 (1,280).

Analysis:

Calcd. for CgeHa N0 5:

C, 65.66; H, 7.84; N, 2.95; S, 6.74

Found: C, 65.27; H, 7.88; N, 2.89; S, 6.86

The ethereal filtrate above was stirred with 200 ml. of percent aqueousacetic acid for 9% hour. The aqueous layer was separated, then extractedonce with ether, and the ether extract discarded. The aqueous layer wasthen cooled, basified with aqueous sodium hydroxide solution andextracted with methylene chloride (four portions of 75 ml. each. Theextracts were combined, washed with water, saturated salt solution,dried by passing the solution through anhydrous sodium sulfate andevaporated to give 22.5 g. of oily material. This material wasrecrystallized from petroleum ether to give 21.4 g. (71 percent yield)of cis-A-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol of meltingpoint 7880 C. Ultraviolet: A max. 225 (1 1,500); 275 (1,500); 283(1,300).

Analysis:

Calcd. for C H NO C, 75.20; H, 9.63; N, 4.62 Found: C, 75.17; H 9.88- N4.47

The above configurations are simplified. For example, a truerrepresentation of the cis form above would be the configurations (X) and(Y) below.

cis trans In the configuration (X) the p-methoxybenzoyl group (at 1) isattached by an axial bond (a) to the cyclohexane moiety (chair form) andthe piperidino group (at 2) by an equatorial bond (e). While this wouldindicate the existence of a cis isomer with reversed grouping, i.e.,p-methoxybenzoyl on an equatorial bond and piperidino on an axial bond,such an isomer is thermodynamically less stable under ordinaryconditions. However, the optical isomers (Y) and (X) of the cis form arestable and thus the simplified cis configuration represents a mixture of(X) and (Y). 1n the trans form, the equatorial-equatorial positions ofthe vicinal substituents is the thermodynamically stable configurationand thus only one trans-p-methoxyphenyl 2-piperidinocyclohexyl ketoneconsisting of two optical forms, as for the cis compound, is obtained.

EXAMPLE 39 Cis-p-methoxyphenyl 2-piperidinocyclohexyl ketone A mixtureof 139 g. (0.6 mole) of 2-(p-methoxybenzoyl)cyclohexanone, 153 g. (1.8moles) of piperidine,

4800 ml. of toluene and 4.02 g. of p-toluenesulfonic acid monohydratewas refluxed for 20 hours in a vessel equipped with an azeotropicseparator. A total of 10.1 ml. of water was collected. The reactionmixture was evaporated to dryness on a steam bath to give a residuewhich was dissolved in 1,200 ml. of ethanol and the thus-obtainedsolution was divided into four equal parts. Each part was hydrogenatedin the presence of 1.5 g. of platinum oxide at an initial pressure of 50pounds of hydrogen. Hydrogenation was stopped after the uptake of 1molar equivalent. The time required for this procedure was 25 minutes to55 minutes. Thereafter, the combined mixture was filtered throughdiatomaceous earth, and the solution was evaporated to dryness. A deepyellow oil was obtained which was dissolved in 1,200 ml. of ether andallowed to stand for 15 minutes. The mixture was thereupon filtered anda precipitate was collected weighing 5.3 g. The ethereal filtrate wasstirred with 1 l. of 10 percent aqueous hydrochloric acid for 45minutes. The acidic layer was separated, filtered and basified with 20percent aqueous sodium hydroxide solution. The resulting oil whichsolidified after a short time was extracted with methylene chloride(five portions of 200 ml. each), the extracts were combined, washed withwater, then with saturated salt solution, dried over anhydrous sodiumsulfate and evaporated to give a crude product of l 16 g.Recrystallization of this crude product from petroleum ether gave 75 g.(42 percent yield) of colorless needles of cis-p-methoxyphenylZpiperidinocyclohexyl ketone having a melting point of 8688 C. Furtherrecrystallization from petroleum ether for analytical purposes gavecis-p-methoxyphenyl 2-piperidinocyclohexyl ketone of melting point86.5-88 C.

Ultraviolet: A max. 217 (11,850 273 (15,800); 278 (15,500).

Analysis:

Calcd. for C H NO C, 75.71; H, 9.03; N, 4.65 Found: C, 76.19; H, 9.19;N, 4.88

EXAMPLE 40 Trans-p-methoxyphenyl 2-piperidinocyclohexy1 ketone Asolution of 68.3 g. (0.227 mole) of cisp-methoxyphenyl2-piperidinocyclohexyl ketone was refluxed for 68 hours in 683 m1. ofpiperidine. The reaction mixture was thereupon evaporated to dryness togive 55 g. of a residual oil which was dissolved in 500 ml. of ether andextracted with four portions of ml. each of 10 percent aqueous aceticacid. The acid extracts were combined, cooled in ice and basified with20 percent aqueous sodium hydroxide solution and thereupon extractedwith four portions of ml. each of methylene chloride. The methylenechloride extracts were combined, washed with saturated salt solution,dried over anhydrous sodium sulfate and evaporated to give 22 g. of acolorless solid which was crystallized from 150 m1. of petroleum ether(boiling range from 30-60 C.) to give 12.05 g. of trans-p-methoxyphenylZ-piperidinocyclohexyl ketone of melting point 100-l01 C. A second cropof 3.5 g. of the same material was also obtained; a total of 23 percentyield. Ultraviolet: A max. 216 (12,900); 271 (15,350).

Analysis:

Calcd. for C ,H, NO

C, 75.71; H, 9.03; N, 4.65 Found: C, 75.28; H, 8.66; N, 4.62

The original ether layer above contained alsol-(p-methoxy-benzoyl)-l-cyclohexene, a yellow oil boiling at l45-155 C.

Analysis:

Calcd. for C H O .7 EXAMPLE 41 Cis-A-a-( p-methoxyphenyl)-2-piperidinocyclohexanemethanol v H (in t A solution of'cis-p-methoxyphenyl Z-piperidinocyclohexyl ketone (3.01 g.; 0.01 mole)in 100 ml. of ethanol was subjected to hydrogenation inthe presence ofplatinum oxide (0.3 g.) atan' initial pressure of 53 pounds of hydrogen.One molar equivalent was absorbed in 25 hours. The mixture was filtered,and the filtrate was evaporated to dryness, giving 3.1 g. of an oilymaterial. A.2 .9-g. portion of this oil was chromatographed over 150 g.of Florisil (anhydrous magnesium silicate) using 150-m1. portions of aneluant of 6 percent acetone-94percent Skellysolve B hexanes. The firstfour fractions containing Since the carbon atom of the methanol group ofa-(p- 'methoxyfphenyl)-2-piperidinocyclohexanemethanol is asymmetric, itis obvious that besides the cis-A-alcohol, the cis-B- alcohol ispossible (Example 42).

EXAMPLE 42" Cis-A- I andcis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol 1 Solidcis-p-methoxyphenyl 2-piperidinocyclohexyl ketone (3.01 g.; 0.01 mole)was added, to an ice-cooled solution of sodium borohydride (3 g.) in 100ml. of ethanol. The reaction mixture was then stirred at roomtemperature (22-25 C.) for a period of .16 hours. It was evaporated todryness in vacuo at 40 C. To. the residue was added 100 ml. of water,and the mixture was then stirred for 30 minutes. The resulting oil wasextracted three times with ether. The ether extracts were combined,washed with water, the water discarded, then washed with four 25-ml.portions of percent aqueous acetic acid. The acidic extract was washedonce with ether, and the ether discarded. It was then cooled in ice andbasified with percent sodium hydroxide solution. The reaction mixturewas then extracted three times with ether, the extracts combined, washedwith water, then with saturated salt solution, dried over anhydroussodium sulfate and evaporated to give 3 g. of an oil. The oily materialwas crystallized from 50 ml. of petroleum ether (boiling range 30-60 C.)to give 1.8 g. ofcis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol, melting point78-80 C.

The filtrate was evaporated todryness, and the residue waschromatographed on 60 g. of Florisil (anhydrous magnesium silicate). Thecolumn of Florisil was eluted twice with 150-m1. portions ofaneluantconsisting of 6 percent acetone and 94 percent Skellysolve Bhexanes; four times with 150-ml. portions of an eluant consisting of 12percent acetone and 88 percent Skellysolve B hexanes; and finally threetimes with 150- ml; portions of a percent acetone-80 percent SkellysolveB hexanes solution, giving 0.576 g. of cis-A-alcohol, which afterrecrystallization from petroleum ether had a melting point of 80-81 C.Elution with 50 percent acetone-50percent Skellysolve B hexanes (fourportions of 150 ml. each) and acetone (two portions of '250 ml. each)gave 0.316 g. ofcis-B-a-(pmethoxyphenyl)-Z-piperidinocyclohexanemethanol, which afterrecrystallization from ether weighed 0.1 g. and had a melting point of135-l 36 C.

These cis alcohols A and B can also be produced from cis-pmethoxyphenylZ-piperidinocyclohexyl ketone by reduction with lithium aluminumhydride.

EXAMPLE 43 Cis-A- andcis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol A solution of0.9 g. (Bmmoles) of cis-p-methoxyphenyl 2 piperidinocyclohexyl ketone in25 ml. of ether was added dropwise during 5 minutes to a solutioncontaining 1 g. of lithium aluminum hydride in 100 ml. of ether..Themixture was stirred during a period of 22 hours and was then decomposedby successive addition of 1 ml. of water, 1 ml. of 15 percent aqueoussodium hydroxide and 3 ml. of water. The resulting suspension wasstirred for a period of 2 hours. It was then filtered and the solidwashed with ether. The combined filtrate and washings were extractedwith three portions of 30 ml. each of 10 percent aqueous acetic acid,and the combined acidic extracts were backwashed once with ether. Theacidic extract was then basified with 15 percent aqueous sodiumhydroxide and extracted three times with ether. The combined etherextracts were washed with water, saturated salt solution, and dried bypassage through anhydrous sodium sulfate. The

resulting dried solution was evaporated to give 0.77 g. of a colorlessoil. This oil was chromatographed over 35 g. of Florisil (anhydrousmagnesium silicate) by eluting with an eluant consisting of 6 percentacetone and 94 percent Skellysolve B hexanes. The first four fractionsof 150 ml. each gave 0.607 g. (67 percent yield) ofcis-A-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol(melting point-81 C.). Further elution with an eluant consisting of 12 percent acetoneand 88 percent Skellysolve B hexanes gave, in four -ml. fractions, 0.209g. of cis-B-a-(p-methoxypheny)-2- piperidinocyclohexanemethanol ofmelting point l34-l35 C. (23 percent yield).

EXAMPLE 44 Trans-C-a-(p-methoxyphenyl)-2-piperidinocyc1ohexanemethanol1n the manner given in Example 41, trans-p-methoxyphenylZ-piperidinocyclohexyl ketone (3.01 g.; 0.01 mole) was hydrogenated inethanol solution in the presence of 0.5 g. of platinum oxide catalyst at53 pounds initialhydrogen pressure. The solution after 138 minutes ofhydrogenation was filtered through Filtercel diatomaceous earth. Thefiltrate was evaporated giving 3 g. of a solid of melting point 14l-l45C. This solid was crystallized from methanol to give 2.5 g. of colorlessneedles of trans-C-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanolof melting point l48-l49 C. A second crop of 0.25 g. of product wasobtained from the filtrate; the total yield was 91 percent. Ultraviolet:225 (12,150); 275 (1,500); 281 (1,300).

Analysis:

Calcd. for G i-1 EXAMPLE 45 20; H, 9.63; N, 4.62 l

5. Found: 5. 8; H, 9.81; N, 4.82

thereupon extracted twice with methylene chloride. The combined extractwas washed with water, saturated salt solution, dried by passage throughanhydrous sodium sulfate and evaporated to give 0.6 g. of a colorlesssolid of melting point 129-l40 C. Crystallization from methanol yielded0.325 g. of recovered starting material of melting point l45l47 C. Thefiltrate was evaporated to dryness and the residue was chromatographedover g. of Florisil (anhydrous magnesium silicate). The columncontaining the Florisil was eluted with 400 ml. of a solution containing6 percent acetone and 94 percent Skellysolve B hexanes. The filtratesfrom the solution were combined and evaporated, and the residue wasrecrystallized from petroleum ether (boiling range 30-60 C.) to give 77mg. of a product melting at 8l82 C., namely trans-D-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol. Ultraviolet: 226 (11,000); 276 1,650); 282 1,450).

Analysis:

Calcd. for C H,,NO,:

EXAMPLE 46 Trans-C- andtrans-D-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol A solutionof trans-p-methoxyphenyl 2-piperidinocyclohexyl ketone (23.9 g.; 0.0795mole) in 575 ml. of ether was added to a solution of 24 g. of lithiumaluminum hydride in 2,400 ml. of ether over a period of 30 minutes. Themixture was then stirred for about hours. It was thereupon decomposedsuccessively with 24 ml. of water, 24 ml. of 15 percent aqueous sodiumhydroxide and 72 ml. of water. The resulting mixture was filtered andthe cake was washed with ether. The combined filtrate and washings wereevaporated to dryness to give 22.5 g. of a colorless oily solid whichupon crystallization from 75 ml. of ethanol gave 13.4 g. oftrans-C-a-(p-methoxyphenyl)-2-pi eridinocyclohexanemethanol of meltingpoint l45- 1 46 C.

The filtrate was evaporated to dryness. The residue was dissolved in 50ml. of methylene chloride and chromatographed over 460 g. of Florisil(anhydrous magnesium silicate). The column containing the Florisil waseluted with 750 ml. of an eluant consisting of 3 percent acetone and 97percent Skellysolve B hexanes. This fraction yielded 81 mg. of solidwhich was discarded; thereupon were taken 19 250-ml. portions using aneluant consisting of 6 percent acetone and 94 percent Skellysolve Bhexanes. These fractions were combined and evaporated to give 5.31 g. ofsolid melting at 80-82 C. Further elution with an eluant consisting of15 percent acetone and 85 percent Skellysolve B hexanes (4 fractions of250 ml. each) gave 0.535 g. of solid melting at 808l C.Recrystallization of the combined material from petroleum ether afforded4.6 g. of trans-D-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanolof melting point 8 l-82 C.

Nuclear magnetic resonance spectrum (in CDCl;,) showed methoxy at 229cps; broad band for benzylic hydrogen centered at 278.5 cps.

Found:

EXAMPLE 47 Cis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol Asolution was prepared having 30.3 g. (0.1 mole) of cis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol in 200 ml. oftrifluoroacetic acid, under cooling with ice. The mixture was thenstirred at room temperature for 20 minutes, giving a greenish solutionwhich was again cooled in ice. To this solution was added 150 g. of icefollowed by 500 ml. of water and then 500 ml. of 20 percent aqueoussodium hydroxide. The mixture was stirred for 15 minutes and wasthereupon extracted with five portions of 200 ml. each of methylenechloride. The methylene chloride extracts were combined, washed withwater, saturated salt solution, then dried by passage through anhydroussodium sulfate and evaporated to Analysis:

Calcd. for C,,H ,NO,:

C, 75.20; H, 9.63; N, 4.62 Found: C, 74.96; H, 9.62; N, 4.55

EXAMPLE 48 a-( 3,4,5-Trimethoxyphenyl )-2-( hexahydrol H-azepinlyl)cyclohexanemethanol hydrochloride OCH;

H 60H; N

A mixture of g. (0.12 mole) of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone,35.6 g. (0.36 mole) of hexamethyleneimine, 960 ml. of toluene and 0.8 g.of ptoluenesulfonic acid was refluxed for 7.5 hours in a nitrogenatmosphere in a vessel equipped with an azeotropic separator. A total of1.8 ml. of water was collected. The mixture was thereupon evaporated todryness, the residue was dissolved in 250 ml. of ethanol andhydrogenated in the presence of 1.2 g. of platinum oxide at an initialpressure of 5 1.5 pounds of hydrogen. Two molar equivalents of hydrogenwere absorbed during 5 hours. The reaction mixture was then filteredthrough diatomaceous earth (Filtercel), and the filtrate was evaporatedto dryness. The thus-obtained residue was dissolved in 400 ml. of ether.The ether solution was stirred with 400 ml. of 10 percent hydrochloricacid for 0.5 hours, and the resulting suspension was filtered. Theobtained solid was washed with ether to give 18.2 g. of material. Thismaterial was crystallized from 250 ml. of methanol to give 16.4 g. of a-3 ,4,5-trimethoxyphenyl )-2-(hexahydrol l-l-azepinlyl)cyclohexanemethanol hydrochloride of melting point 244-246 C.

Ultraviolet: sh 288 (8,250); 268 (757); 276 (608).

Analysis:

Calcd. for C rr nza-H01;

C, 63.83; H, 8.77; Cl, 8.56; N, 3.38 Found: C, 63.95; H, 9.13; Cl, 8.47;N, 3.58 Workup of the aqueous hydrochloric acid filtrate above providedanother 0.7 g. of a-(3,4,5-trimethoxyphenyl)-2- hexa-hydrol l-l-azepinl-yl)cyclohexanemethanol v hydrochloride of melting point 242-243 C.;thus a total yield of 34 percent.

EXAMPLE 49 l-l-azepinl reaction mixture was added a solution of 102 g.0.6 mole) of 1 p-anisoyl chloride in 240 ml. of purified chloroformduring a period of 2 hours while keeping the temperature between 5 to C.A suspension resulted which was stirred for a period of about hours atroom temperature. The suspension was thereupon filtered, and theprecipitate washed with ether, the ether wash being discarded. Theprecipitate was 46.8 g. of triethylamine hydrochloride of melting point3-254 C.

' The chloroform filtrate was evaporated to dryness. The resultingresidue was dissolved in 900 ml. of ethanol and hydrogenated in threeportions, each in the presence of l g. of platinum oxide at a hydrogenpressure of about 50-52 pounds. After the absorption of about 80 percentof the hydrogen had taken place, the hydrogenation stopped and another 1g. of platinum oxide was added. Two molar equivalents of hydrogenwereabsorbed during 22 hours. The resulting thick suspension was filteredand the precipitate washed with ethanol. The moist cake was refluxedwith 1,500 ml. of ethanol, .filtered and allowed to crystallize. Thefirst crop of crystals amounted to 80.7 g.,ofcis-A-a-(p-methoxyphenyl)-2- (hexahydrolH-azepinl-yl)cyclohexanemethanol hydrochloride of melting point of 230-23 1 C. Asecond crop of 20 g. was also collected. Further recrystallization didnot change the melting point of the product.

Ultraviolet: )1 maxy226 12,150); 276 1,550); 282 1,350).

Analysis:

Calcd. for c,,,H ,,No,-Hcl= C, 67.87; H, 9. l2; Cl, 10.02; Found: C,67.27; H, 9.14; Cl,

EXAMPLE 50a(p-Trifluoromethylphenyl)-2-(hexahydro-lH-azepin-lyl)cyclohexanemethanolhydrochloride In the mariner given in Example 49, 0.1 mole oftriethylamine and 0.1 mole of l-hexamethyleneimino-lcyclohexene wasreacted irichloroform solution with 0.1 mole of p-trifluoromethylbenzoylchloride. The resulting product was hydrogenated in 300 ml. of methanolin the presence of l g. of platinum oxide. Two molar equivalents ofhydrogen were absorbed in 3.5 hours. The hydrogenation reaction mixturewas filtered through diatomaceous earth (Filtercel) and the filtrateevaporated to dryness. The resulting solid was suspended in 200 ml. ofether and 200 ml. of 10 percent aque ous acetic acid, and the suspensionwas stirred for a period of 3.5 hours. The suspension was then filtered,and the solid washed with water followed by ether. Thirteen andfour-tenths g. of solid was thus obtained which was recrystallized frommethanol giving a-(p-trifluoromethylphenyl)-2-(hexa-hydro-1H-azepin-l-yl)cyclohexanemethanol hydrochloride of melting point 263-264C. v

Ultraviolet: A max. 216 (8,050); 252 (298); 257 (357); 263(364);269(290).

Analysis:

Calcd. for C ,,H F NO-HC1:

C, 61.29; H, 7.46; Cl, 9.05; F, 14.54; found: C, 60.89; H, 7.58; Cl,9.17;

EXAMPLE 51 N, 3.57 F, 13.96; N, 3.66

ml. of ethanol, heated to reflux, filtered and the solution allowed tocrystallize. Filtration yielded 12.25 g. of a-(pchlorophenyl )-2-(hexa-hydrol H-azepin- 1 -yl)cyclohexanemethanol hydrochloride of meltingpoint 274-275 C. Ultraviolet: A max. 221 (10,000); sh 226 (8,200); 252(182); 258 (210); 267 (260); 275 (193).

Analysis:

Found: N, 3.98

EXAMPLE 52 a-Phenyl-2-( hexahydrolH-azepinl -yl)cyclohexanemethanolhydrochloride in the manner given in Example 49, 0.1 mole oftriethylamine, 0.1 mole of l-hexamethylimino-l-cyclohexene and 0.1 mole14 g.) of benzoyl chloride were reacted, and the reaction producthydrogenated in methanol in the presence of platinum oxide for a periodof 2.5 hours. The mixture was filtered, evaporated to dryness and thesolid residue was suspended in 200 ml. of ether and 200 ml. of 10percent aq ueous acetic acid. The mixture was stirred for 0.5 hour andthe resulting suspension filtered yielding a solid which was washed withwater followed by ether. The thus-obtained product, 3.6 g., wasrecrystallized from methanol to give 2.8 g. of a-phenyl- 2-( hexahydro-1 l-l-azepin- 1 -yl )cyclohexanemethanol hydrochloride of melting point276277" C. Ultraviolet: A max. 247 (107.); 252 (130); 257 (178); 263(130);267(91). 7

Analysis:

Calcd. for C H NO'HCl:

C, 70.45; H, 9.34; CI, 10.95; N, 4.33 Found: C, 70.22; H, 8.94; CI,11.03; N, 4.45

EXAMPLE 53 a-( 3,4-Methylenedioxyphenyl )-2-(hexahydrol l-l-azepin- 1yl)cyclohexanemethanol hydrochloride 1 A solution of piperonyloylchloride in ml. of chloroform was added during 1.5 hours with coolingand stirring to a solution of l-hexamethyleneimino-l-cyclohexene (53.6g.; 0.3 mole) and 30.3 g. (0.3 mole) of triethylamine in 126 ml. ofchloroform at a'temperature below 10 C. The reaction mixture was thenstirred for about 20 hours at a temperature between 23-26 C. Thethus-obtained suspension was filtered to give 23 g. of triethylaminehydrochloride melting at 252254 C. The filtrate was evaporated todryness, the residue was dissolved in 600 ml. of ethanol andhydrogenated in the presence of 3 g. of platinum oxide'at an initialpressure of 52.5 pounds of hydrogen. After 6 hours, a l g. quantity ofplatinum oxide catalyst was added and hydrogenation continued foranother 16 hours. The resulting suspension was filtered and the solid,consisting of the product and catalyst, was refluxed in 1,800 ml. ofethanol; this suspension was. filtered, evaporated to 900 ml. andallowed to crystallize, yielding 50 g. of a-( 3,4-methylenedioxyphenyl)-2-(hexahydro-ll-l-azepin-1-yl)cyclohexanemethanol hydrochloride of melting point 235236 C.

Work-up of the filtrate by evaporation and stirring with 400 ml. of 10percent aqueous acetic acid and 450 ml. of ether gave another 10 g. ofsolid material which after recrystallization from ethanol gave 5 g. ofa-(3,4-methylenedioxyphenyl)- 2-(hexa-hydrol l-l-azepinlyl)cyclohexanemethanol hydrochloride of melting point 233-234 C.

Ultraviolet: A max. 235 (4,150); 286 (4,050).

Analysis:

Calcd. for c,,,i-l,,,No,-Hcl:

C, 65.29; H, 8.22; Cl, 9.64; N, 3.81

Found: C, 65.18; H, 8.38; CI, 9.93; N, 3.79

The above compound is useful as a diuretic and oral antidiabetic agent.

EXAMPLE 54 a-( 3 ,4-Dimethoxyphenyl )-2-( hexahydro- 1 H-azepin- 1 -yl)cyclohexanemethanol hydrochloride In the manner given in Example 53,l-hexamethyleneiminol-cyclohexene was reacted with 3,4-dimethoxybenzoylchloride (53.6 g.; 0.3 mole) in the presence of triethylamine. Theresulting product was hydrogenated in the presence of platinum oxide andthe mixture was worked up as in Example 53 giving 52.2 g. ofa-(3,4-dimethoxyphenyl)-2-(hexahydrolH-azepin-l-yl)cyclohexanemethanolhydrochloride of melting point 225-228 C. in the first crop. Additionalmaterial was obtained by the work-up of filtrates with acetic acid andether. A total yield of about 50 percent was obtained. The analyticalsample, prepared by recrystallization from ethanol, gavea-(3,4-dimethoxyphenyl)-2-(hexahydro-lH-azepin-lyl)cyclohexanemethano1hydrochloride of melting point 225226 C. Ultraviolet: A max. 230(8,550); 279 (2,950); sh 285 (2,550).

24; C, 65.88; H, 9.19; Cl, 3

9. Found: 9.

EXAMPLE 55Cis-B-a-(p-methoxyphenyl)-2-(hexahydro-lH-azepin-lyl)cyclohexanemethanoland the hydrochloride thereof To 240 ml. of trifiuoroacetic acid, cooledto 5 C. was added, all at once, 38 g. (0.12 mole) ofcis-A-a-(p-methoxyphenyl )-2-( hexahydrol H-azepin- 1-yl)cyclohexanemethanol with stirring. The mixture was kept stirring for20 minutes whereby the temperature reached about 40 C. Thereupon, thesolution was cooled, ice was added, followed by 600 ml. of water andthen 600 ml. of 20 percent aqueous sodium hydroxide. The mixture wasthen extracted with five 200-ml. portions of methylene chloride. Theextracts were combined, washed with saturated salt solution, dried bypassing through anhydrous sodium sulfate, and the filtrate evaporated togive 37.9 g. of a yellowish oil. This oil was dissolved in 150 ml. ofpetroleum ether (boiling range 30-60 C.) and allowed to crystallize inthe refrigerator overnight; 13.6 g. of crystals were recovered byfiltration. These crystals were recrystallized from 50 ml. of ether togive 10.1 g. of cis-B-a-(p-methoxyphenyl)-2-(hexahydro-1H-azepin-l-y1)cyclohexanemethanol of melting point 94-95.5 C.Ultraviolet: A max. 225 (12,750); 275 (1,550); 281 (1,350).

Analysis:

Calcd. for C H NO Found:

The hydrochloride ofcis-B-a-(p-methoxyphenyl)-2-(hexahydro-lI-I-azepin-l-yl)cyclohexanemethanolwas prepared with 1.5 N ethereal hydrogen chloride. After twocrystallizations from methanol-ether, colorless needles were obtainedmelting at 188-l 89 C.

Ultraviolet: A max. 226 (12,700); 275 (1,450); 281 (1,250).

Analysis:

Calcd. for C H ,N0,-HCl:

C, 67.87; H, 9.12; Cl, Found: C, 67.24; H, 9.36; Cl,

Analysis:

Calcd. for C H NO HCI:

C, 68.26; H, 8.59; Cl, 10.08; N, 3.98 Found: C, 67.92; H, 8.55; Cl,10.06; N, 4.05

EXAMPLE 56 a-(3,4,5-Trimethoxyphenyl)-2-piperidinocycloheptane methanolhydrochloride A. l-Piperidino- 1 -cycloheptene.

A mixture of 224.2 g. (2 moles) of cycloheptanone, 340 g. (4 moles) ofpiperidine, 400 ml. of benzene and 2.2 g. of ptoluenesulfonic acid wasrefluxed for a period of 16 hours in a nitrogen atmosphere, using anazeotropic separator. A total of 5 ml. of water was collected. Sincethis was less than the calculated amount of water produced during thereaction, the separator was replaced with a Soxhlet extractor containing322 g. of crystalline sodium aluminum silicate, Na [(Al o (SiO [Lindemolecular sieve, Type 4A; see The Merck Index, Merck and Co., Inc. 1960,Seventh Edition, page 1,592], and the mixture was refiuxedfor 3 days.After the solvent was removed by distillation from the reaction mixture,319.7 g. of l-piperidino-l-cycloheptene of boiling point -l3 1 C. at 17mm. (89 percent yield) was obtained.

B. a-(3,4,5-Trimethoxyphenyl)-2-piperidinocyclohep tanemethanolhydrochloride In the manner given in Example 49, Part B, 23 g. (0.1mole) of 3,4,5-trimethoxybenzoyl chloride, 17.9 g. (0.1 mole) oflpiperidino-l-cycloheptene and triethylamine (0.1 mole) were reacted atlow temperature in a chloroform solution. The resulting product washydrogenated in methanol for a period of 3 hours during which 2 molarequivalents of hydrogen were consumed. The resulting reaction mixturewas then filtered and evaporated, and the residue stirred with ml. ofwater and 150 ml. of methylene chloride for a period of 0.5 hour. Themethylene chloride layer was separated and stirred with 250 ml. of 10percent aqueous hydrochloric acid for one-half hour. The resultingsuspension was filtered and the solid washed with water to give 7.5 g.of a-(3,4,5-trimethoxyphenyl)-2-piperidinocycloheptanemethanolhydrochloride of melting point 237-238 C. This material wasrecrystallized from methanol to givea-(3,4,5-trimethoxyphenyl)-2-piperidinocycloheptanemethanolhydrochloride of melting point 243-244 C.

Ultraviolet: sh 266 (8,250); sh 234 (6,800); A max. 270 (782); sh 278(546).

Analysis:

Calcd. for C,,H,,,,NO,-HC1:

C, 63.82; H, 8.77; Cl, 8.5 Found: C, 63.43; H, 8.85; Cl, 8.6

The work-up of the methylene chloride layer gave 1.5 g. of cycloheptyl3,4,5-trimethoxyphenyl ketone of melting point 7677 C. in colorlesscrystalline plates.

Analysis:

Calcd. for C H O Found: C, 69.64; H, 8.24

EXAMPLE 5 7 a-( 3 ,4,5-Trimethoxyphenyl )2-(1-pyrolidinyl)cyclohexanemethanol and hydrochloride A mixture of 17.5 g.(0.06 mole) of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone, 12.8 g. (0.18mole) of pyrrolidine and 480 ml. of benzene was refluxed for 1.25 hoursusing an azeotropic separator; 1.5 ml. of water was collected. Themixture was evaporated to dryness to give a yellow oil. A small samplewas crystallized twice from ether to give yellow prisms melting at1l8120 C. and constituting 3,4,5-trimethoxyphenyl 2-( 1-pyrrolidinyl)-l-cyclohexen-l-yl ketone. Ultraviolet: in ether A max. 262 (11,50 358(5,500); in ethanol sh 220 17,000); 269 (7,700); 372 (7,050).

Analysis:

" Calcd. for C NO4 C, 69.54; H, 7.88; N. 495

Found: C, 69.91; H, 8.08; N, 3.76

The crude 3,4,5-trimethoxyphenyl 2-( l-pyrrolidinyl)-lcyclohexen-l-ylketone was dissolved in 250 ml. of ethanol and hydrogenated in thepresence of 0.6 g. of platinum oxide. Two molar equivalents of hydrogenwere taken up in 6 hours. The mixture was then filtered throughdiatomaceous earth and the filtrate evaporated to dryness. The residuewas stirred with 200 ml. of 10 percent aqueous hydrochloric acid and 250ml. of ether for 0.5 hour. The aqueous layer was separated, extractedwith ether, basified with sodium bicarbonate and extracted with fourl25-ml. portions of methylene chloride. The methylene chloride extractswere combined, washed with water, then with saturated salt solution,dried by passing through anhydrous sodium sulfateand evaporated to give16.5 g. of solid. This solid was recrystallized from ether to give 9.7g. of a-(3,4,5-trimethoxyphenyl)-2-( l-pyrrolidinyl)cyclohexanemethanolof melting point l21-122 C. A second crop of 2 g. of the alcohol wasobtained with a melting point of 1 l9l20 C. The total yield was 56percent. Ultraviolet: .rh 226 (9,200); A max. 269 (744); sh 280 (542).

Analysis:

Calcd. for C,,,H ,NO

Found:

Analysis:

Calcd. for C,, H ,NO ,-HCI:

C, 62.24; H, 8.36; Cl, 9.19; N, 3.63 Found: C, 62.31; H, 8.82; Cl, 9.153.65

EXAMPLE 58 3 ,4,5 -Trimethoxy-a-( Z-pipe ridinocyclopentyl)benzylalcohol [a-( 3 ,4,5-trimethoxyphenyl)-2-piperidinocyclopentanemethanol]A. 3,4,5-Trimethoxyphenyl ketone.

A solution of 15.1 g. (0.1 mole) of l-piperidino-l-cyclopentene wasadded, in a nitrogen atmosphere, with ice cooling, to a solution of 10.1g. (0.1 mole) of triethylamine in 42 ml. of chloroform (purified bypassage through a column of basic alumina). To this solution was added asolution of 23.0 g. (0.1 mole) of 3,4,5-trimethoxybenzoyl chloride in 40ml. of chloroform, over a period of 1.5 hours, while the temperature ofthe reaction mixture was kept at 5-10 C. The mixture was then stirredovernight at room temperature (22-25 C.) and was filtered to give 6.91g. of triethylamine hydrochloride. The filtrate was evaporated todryness at 50 C. The residue was dissolved in 250 ml. of ethanol, 12 g.(0.2 mole) of acetic acid and 1 g. of platinum oxide were added andhydrogenation was carried out at an initial pressure of 51 pounds. Twomoles of hydrogen were taken up during 1 hour and 28 minutes; more than90 percent of the calculated hydrogen was absorbed in the first halfhour. The mixture was then filtered and evaporated to dryness. A mixtureof 100 ml. of ether and 100 ml. of percent aqueous hydrochloric acid wasadded, and the obtained reaction mixture was stirred for 1.5 hours. Thelayers were separated and the aqueous layer was extracted once withether. The ether extracts were washed with water to give the neutrallayer." The acidic layer was cooled in ice and basified with 20 percentaqueous sodium hydroxide. it was extracted twice with ether, thecombined ether extract 2'piperidinocyclopentyl was washed with water,saturated salt solution, dried by passage through anhydrous sodiumsulfate and evaporated to give 14.6 g. of a brown oil which solidifiedon standing in vacuo overnight. The solid was dissolved in 150 ml. ofpetroleum ether (boiling range between 30-60 C.) and 20 ml. of ether andcooled with ice for 2 hours. The resulting suspension was decanted, thusproviding solid A and filtrate B. Filtrate B was evaporated to abouthalf the volume and cooled. The resulting solid, 1.2 g. of melting pointl20-l 30 C., was removed by filtration. Recrystallization of this solidfrom ether gave colorless needles of melting point 133.5-l 345 C. Themelting point of this material was not changed by recrystallization fromether. Ultraviolet, infrared and NMR spectra and also carbon, hydrogenand nitrogen analysis indicated that this product was a mixture.

Solid A and the residue from filtrate B were combined to give 13.3 g. ofa yellow solid. This solid was dissolved in 50 ml. of benzene andchromatographed over 400 g. of neutral alumina, taking six benzenefractions of 250 ml. each. Fraction 2 contained 2.378 g. of materialwhich was crystallized from 20 ml. of Skellysolve B hexanes to give 1.5g. of 3,4,5-trimethoxyphenyl Z-piperidinocyclpentyl ketone of meltingpoint 7980 C. Ultraviolet: A max. 217 (29,400); 283 (10,700).

Analysis:

Calcd. for C, H,,,N0,:

Found:

The above neutral layer contained a solid fraction of 8.78 g. whichafter recrystallization from Skellysolve B hexanes gave 6.8 ofcyclopentyl 3,4,5trimethoxyphenyl ketone of melting point 46-47.5 C.

B. 3,4,5-Trimethoxy-a-(Z-piperidinocyclopentyl)benzyl alcohol A solutionof 1.2 g. (3.48 mmoles) of 3,4,5-trimethoxyphenyl2-piperidinocyclopentyl ketone in 25 ml. of ether was added over aperiod of 5 minutes to a solution of 1.2 g. of lithium aluminum hydridein 100 ml. of ether, and the mixture was stirred for 21 hours. It wasthen decomposed by successive addition of 1.2 g. ofwater, 1.2 ml. of 15percent aqueous sodium hydroxide and 3.6 ml. of water. The thus-obtainedreaction mixture was stirred for a period of 2 hours giving asuspension. This suspension was filtered and the solid washed withether. The ether washing and the ether filtrate were combined, dried bypassage through anhydrous sodium sulfate and evaporated to give 1.2 g.of an oil. The oil was chromatographed over 48 g. of Florisil (anhydrousmagnesium silicate). Elution with five 100-m1. portions of a mixtureconsisting of 10 percent acetone and 90 percent Skellysolve B hexanesgave 0.136 g. of an oil. Elution with five portions of 100 ml. each of20 percent acetone-80 percent Skellysolve B hexanes mixture gave 0.582g. of oil. After standing in vacuo for one week, the oil crystallized togive a solid of melting point -88 C. This solid was recrystallized fromether-petroleum ether to give a 3,4,5-trimethoxy-a-(Z-piperidinocyclopentyl)benzyl alcohol melting at 9 l-92C. Ultraviolet: sh 224 (9,100); sh 234; sh 269 (849); sh 278 (660).

Analysis:

Calcd. for CZQHMNO4:

C, 68. Found: C, 68.

Further elution with 30 percent acetone-70 percent Skellysolve B hexanes(five portions of ml. each) gave 0.140 g. and elution with 50 percentacetone-50 percent Skellysolve B hexanes mixture (five portions of 100ml. each) gave 0.170 g. of solids. A 75 percent acetone-25 percentSkelly-solve B hexanes mixture (five portions of 100 ml. each) gave0.087 g. and elution with acetone (two portions of 100 ml. each) gave0.154 g. of solids..These solid fractions were combined andrecrystallized from petroleum ether (boiling range 30-60 C.)

EXAMPLE 59 3,4,5-Trimethoxy-a-(Zpyrrolidinocyclopentyl)benzyl alcohol[a-(3,4,5-trimethoxyphenyl)-2-pyrrolidino-cyclopentanemethanol] Amixture of 8.35 g. (0.03 mole) of2-(3,4,5-trimethoxybenzoyl)cyclopentanone, 6.5 g. (0.09 mole) ofpyrrolidine, 240 ml. of benzene and 0.2 g. of p-toluenesulfonic acid wasrefluxed under a nitrogen atmosphere for-21 hours using an azeotropicseparator; 0.5 ml. of water was collected. The solution was evaporatedto dryness, 3,4,5-trimethoxyphenyl 2-pyrrolidino-l-cyclopenten-1-y1ketone being obtained as a residue. This residue was dissolved in 100ml. of methanol and hydrogenated in the presence of 0.3 g. of platinumoxide at an initial pressure of 54 pounds. One molar equivalent ofhydrogen was taken up over a period of 4 hours whereupon thehydrogenation was stopped. The mixture was filtered through diatomaceousearth, and the filtrate evaporated to dryness, 3,4,5-trimethoxyphenyl2-pyrrolidinocyclopentyl ketone being obtained as a reside. One-half ofthis product (5 g.; 0.015 mole) was dissolved in 100 ml. of benzene.This solution was added during minutes to a solution of 5 g. of lithiumaluminum hydride in 200 ml. of ether, and the mixture was refluxed withstirring for a period of 3 hours. It was then decomposed by successivelyadding 5 ml. of water, 5 ml. of percent aqueous sodium hydroxide and 15ml. of water. The suspension was filtered, and the solid washed withether. The filtrate and the ether washings were combined, extracted with10 percent hydrochloric acid (four portions of 50 ml. each) and theacidic extracts were basified by the addition of aqueous sodiumhydroxide. The basified solution was extracted with four portions (each50 ml.) of methylene chloride. The methylene chloride extracts werecombined, washed with water, then with saturated salt solution, dried bypassage through anhydrous sodium sulfate and evaporated to give 4.5 g.of a yellow oil. This yellow oil was dissolved in ml. of methylenechloride and chromatographed over 200 g. of Florisil (anhydrousmagnesium silicate). The elution was carried out with five portions of200 ml. each of 50 percent acetone-50 percent Skellysolve B hexanes. Theeluates were concentrated to give 0.41 g. of solid which wasrecrystallized from Skellysolve B hexanes to give3,4,5-trimethoxy-a-(2-pyrrolidinocyclopentyl)benzyl alcohol of meltingpoint 85-86 C Ultraviolet: sh 227 (9,300); A max. 269 (788); sh 278(573). NMR showed H on carbon bearing the OH as a doublet centered at316.5 cps 3 cps).

Analysis:

Calcd. for C, H NO,:

C, 68.03; H, 8.71; N, 4.18 Found: C, 67.50; H, 8.73; N, 4.43

Elution of the above column with five portions of 200 ml. each ofacetone gave after evaporation 0.58 g. of a solid, which wascrystallized from ether and thereupon from tetrahydrofuran-Skellysolve Bhexanes to give isomeric 3,4,5-trimethoxy-a-(2-pyrrolidinocyclopentyl)benzyl alcohol of melting point147-148 C.

Ultraviolet: sh 225 (8,950); A max. 270 1,100); sh 227 (567). NMR showedH on carbon bearing the OH as a doublet centered at 291 cps (j= 5 cps).

Analysis:

Calcd. for C H NQ:

C, 68.03; H, 8.71; N, 4.18 Found: C, 67.70; H, 8.90; N, 4.25

EXAMPLE 60 p-Ethoxyphenyl 2-piperidino-1-cyclohexen-1-yl ketone In themanner given in Example 31, Z-(p-ethoxybenzoyl)cyclohexanone was reactedwith piperidine in the presence of p-toluene sulfonic acid to givep-ethoxyphenyl 21- piperidinol -cyclohexen- 1 -yl ketone.

EXAMPLE 61 p-Benzyloxyphenyl 2-pyrrolidino- 1 -cyclohexen- 1 -yl ketoneIn the manner given in Example 31, 2-(p-benzyloxybenzoyl)-cyclohexanonewas reacted with pyrrolidine in the presence of p-toluenesulfonic acidto give p-benzyloxyphenyl 2-pyrrolidino-1-cyclohexen- 1 -yl ketone.

EXAMPLE 62 p-Benzyloxyphenyl Z-piperidino-l-cyclohexen1-yl ketone 1n themanner given in Example 31, Z-(p-benzyloxybenzoyl)-cyclohexanone wasreacted with piperidine in the presence of p-toluenesulfonic acid togive p-benzyloxyphenyl Z-piperidino- 1 -cyclohexen 1 -yl ketone.

EXAMPLE 63 p-( 2-Hydroxyethoxy)phenyl 2-piperidino-1-cyclohexen l-ylketone In the manner given in Example 31,2-[p-(2-hydroxyethoxy)-benzoyl]cyclohexanone was reacted with piperidinein the presence of p-toluenesulfonic acid to givep-(2-hydroxyethoxy)phenyl 2-piperidinol-cyclohexen-l-yl ketone.

EXAMPLE 64 o-Methoxyphenyl Z-piperidino-l-cyclohexen-l-yl ketone In themanner given in Example 31, 2-(o-methoxybenzoyl)cyclohexanone wasreacted with piperidine in the presence of p-toluenesulfonic acid togive o-methoxyphenyl 2- piperidino- 1 -cyclohexen- 1 -y1 ketone.

EXAMPLE 65 o-Hydroxyphenyl Z-piperidino-l-cyclohexen-l-yl ketone 1n themanner given in Example 31, Z-(o-hydroxybenzoyl)cyclohexanone wasreacted with piperidine in the presence of p-toluenesulfonic acid togive o-hydroxyphenyl 2- piperidino- 1 -cyclohexen- 1 -yl ketone.

EXAMPLE 65A p-Hydroxyphenyl 2-piperidino- 1 -cyclohexen- 1 -yl ketone Inthe manner given in Example 31, 2-(p-hydroxybenzoyl)cyclohexanone wasreacted with piperidine in the presence of p-toluenesulfonic acid togive p-hydroxyphenyl 2- piperidino-l-cyclohexen-1-yl ketone.

EXAMPLE 66 2-Methoxy-4-methylphenyl 2-piperidino- 1 -cyclohexenl -ylketone.

In the manner given in Example 31, 2-(2-methoxy-4-methylbenzoyl)cyclohexanone was reacted with piperidine in the presenceof p-toluenesulfonic acid to give 2-methoxy-4- methylphenylZ-piperidino-l-cyclohexen-1-yl ketone.

EXAMPLE 67 EXAMPLE 68 p-Trifluoromethylphenyl ketone 2-piperidino- 1-cyclohexenl -yl In the manner given in Example 31,Z-(p-trifluoromethylbenzoyl)cyclohexanone was reacted with piperidine inthe presence of p-toluenesulfonic acid to give ptrifluoromethylphenyl2-piperidino-l-cyclohexcnl-yl ketone.

EXAMPLE 69 p-Allyloxyphenyl Z-piperidino- 1 -cyclohexenl -yl ketone Inthe manner given in Example 31, 2-(p-allyloxybenzoyl)- cyclohexanone wasreacted with piperidine in the presence of p-toluenesulfonic acid togive p-allyloxyphenyl Z-piperidinol-cyclohexen-1-yl ketone.

EXAMPLE 70 p-( Methylcarbamoyloxy)phenyl Z-piperidinol -cyclohexen- 1-y1 ketone In the manner given in Example 31,Z-[p-(methylcarbamoyloxy)-benzoyl]cyclohexanone was reacted withpiperidine in the presence of p-toluenesulfonic acid to give p-(methylcarbamoyloxy)phenyl 2-piperidinol -cyclohexenl -y] ketone.

EXAMPLE 7l 3 ,4-Methylenedioxyphenyl 2-( hexahydrol I-I-azepin l -yll-cyclohexenl -yl ketone In the manner given in Example 31,2-(3,4-methylenedioxybenzoyl)cyclohexanone was reacted withhexamethylencimine in the presence of p-toluenesulfonic acid to give 3,4-methylenedioxyphenyl Z-(hexahydrol I-l-azepin- 1- yl)- l-cycIohexen-l-yl ketone.

EXAMPLE 72 p-Chlorophenyl 2-(2-isopropylpyrrolidino)-l-cyclohexenl-ylketone.

In the manner given in Example 31, 2-(p-chlorobenzoyl)- cyclohexanonewas reacted with 2-ispropylpyrrolidine in the presence ofp-toluenesulfonic acid to give p-chlorophenyl 2- (2-isopropylpyrrolidino1 -cyclohexenl -yl ketone.

EXAMPLE 73 p-Hydroxyphenyl 2-octamethyleneimino- 1 -cyclohexenl -ylketone v In the manner given in Example 31, 2-(p-hydroxybenzoyl)-cyclohexanone was reacted with octamethyleneimine in the presence ofp-toluenesulfonic acid to give p-hydroxyphenyl 2- yl ketone;3,5diiodophenyl 2-( 3-methylpiperidino)- I cyclohexen- 1 -y] ketone;2-methoxy-4-chlorophenyl 2- piperidinol -cyclohexenl-yl ketone;2-methyl-4- trifluoromethylphenyl 2-piperidinol-cyclohexen-1-yl ketone;3,4-dipropylphenyl 2-pyrrolidino-l-cyclohepten-l-yl ketone; 2 ,5-dichlorophenyl 2-(hexahydrol l-I-azepin- 1 -yl 1 cyclohepten-l-ylketone; 3,4-dichlorophenyl 2-(3-methylpiperidino)-l-cycloocten-l-ylketone; p-propoxyphenyl 2-(4- butylpiperazino)-l-cycloocten-l-yl ketone;2,5-diiodophenyl 2-( 2-methylhexamethyleneimino)- l -cycloheptenl -ylketone; 3-fluorophenyl 2-pyrrolidino-l-cyclopenten-l-yl ketone; 2-hexylphenyl 2-piperidino-l-cyclopenten-l-yl ketone; 3-pen- 30 tylphenylZ-piperidino- 1 -cyclohexenl -yl ketone; 2-butylphenyl 2-morpholinol-cyclohexen- 1 -y] ketone; 2-

propylphenyl 2-( l,2,3,4-tetrahydro-l-quinolyl)-1-cyclohepten- 1 -ylketone; 3-ethylpheny1 Z-pipen'dinol -cycloocten- 1 -yl ketone;2-methoxy-5-bromophenyl 2-pyrrolidino-l-cyclopenten- 1 -y1 ketone;phenyl 2-octamethyleneiminol -cycloocten-l -yl ketone; phenyl2-(2,3,6-trimethylmorpholino)-l-cyclohepten- 1 -yl ketone; and the like.

EXAMPLE 74 a-(p-Ethoxyphenyl)-2 hydrochloride In the manner given inExample 32, p-ethoxyphenyl 2- piperidino-l-cyclohexen-l-yl ketone washydrogenated in the presence of platinum oxide to givea-(p-ethoxyphenyD-Z- piperidinocyclohexanemethanol recovered ashydrochloride;

-piperidinocyclohexanemethanol melting point 22 l -222 C.

EXAMPLE 75 a-(p-Benzyloxyphenyl)-2-pyrrolidinocyclohexanemethanol In themanner given in Example 32, p-benzyloxyphenyl 2-pyrrolidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence ofplatinum oxide to give a-(p-benzyloXyphenyl)-2-pyrrolidinocyclohexanemethanol.

EXAMPLE 76 Cis-A-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanolIn the manner given in Example 32, p-benzyloxyphenyl 2-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence ofplatinum oxide to givecis-A-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanol of meltingpoint 148.5-149.5 C.

In the same manner, catalytic hydrogenation of cisbenzyloxyphenyl2-piperidinocyclohexyl ketone (Example 88) gives the same product.

EXAMPLE 76A Cis-B-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanoland hydrochloride thereof In the manner given in Example 47,cis-A-a-(p-benzyloxyphenyl)-2 piperidinocyclohexanemethanol wasconverted by means of trifluoroacetic acid tocis-B-a-(p-benzyloxyphenyl)- 2-piperidinocyclohexanemethanol of meltingpoint 129130 C.

This base was treated with ethereal hydrogen chloride, to obtaincis-B-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanolhydrochloride of melting point 238-240 C.

EXAMPLE 77 a-[ p-(2-l-lydroxyethoxy)phenyl]-2-piperidinocyclohexanemethanol hydrochlorideIn the manner given in Example 32, p-(2-hydroxyethoxy)- phenylZ-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presenceof platinum oxide to give a-[p-(2-hydroxyethoxy)-phenyl]-2-piperidinocyclohexanemethanol recovered ashydrochloride of melting point 196198 C.

The hydrochloride can be converted to the free base, and the latter canbe reacted with trichloroacetic acid to give the correspondingtrichloroacetic acid salt, useful as a herbicide, for example, againstJohnson grass, yellow foxtail, green foxtail, Bennuda grass and quackgrass.

EXAMPLE 78 a-(o-Methoxyphenyl)-2-piperidinocyclohexanemethanolhydrochloride In the manner given in Example 32, o-methoxyphenyl 2-piperidino-l-cyclohexen-l-y1 ketone was hydrogenated in the presence ofplatinum oxide to give a-(o-methoxypheny1)-2-piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 79 a-(o-Hydroxyphenyl)-2-piperidinocyclohexanemethanol In themanner given in Example 32, o-hydroxyphenyl 2-piperidinol-cyclohexen-l-yl ketone was hydrogenated in the presence ofplatinum oxide to give a-(o-hydroxyphenyl)-2-piperidinocyclohexanemethanol of melting point l22-122.5 C.

The above compound is useful as a diuretic.

EXAMPLE 79A EXAMPLE 79BCis-B-a-(p-hydroxyphenyl)-2-piperidinocycl0hexanemethanol In the mannergiven in Example 47,cis-A-a-(p-hydroxyphenyl)-2-piperidinocyclohexanemethanol was convertedby means of trifluoroacetic acid to cis-B-a-(p-hydroxyphenyl)-2-cyclohexanemethanol of melting point l82l 83 C.

The above compound is useful as a diuretic.

EXAMPLE 8O a-(2-Methoxy-4-methylphenyl)-2-piperidinocyclohexanemethanolhydrochloride In the manner given in Example 32, 2-methoxy-4-methylphenyl Z-piperidino-l-cyclohexen-l-yl ketone was hydrogenated inthe presence of platinum oxide to give a-(2-methoxy-4-methylphenyl)-2-piperidinocyclohexanemethanol recovered ashydrochloride; melting point 25 l252 C.

EXAMPLE 81 a-( 3 ,5-Dimethyl-4-methoxyphenyl)-2-piperidinocyclohexanemethanol hydrochloride In the manner given inExample 32, 3,5-dimethyl-4-methoxyphenyl 2-piperidin0-1-cyclohexen-l-ylketone was hydrogenated in the presence of platinum oxide to give a-(3,5-dimethyl-4-meth0xyphenyl)-2-piperidinocyclohexanemethanol recoveredas hydrochloride.

EXAMPLE 82 a-( p-Trifl uoromethylphenyl)-2-piperidinocyclohexanemethanol hydrochloride In the manner given inExample 32, p-trifluoromethylphenyl Z-piperidino-l-cyclohexen-l-ylketone was hydrogenated in the presence of platinum oxide to givea-(ptrifluoromethylphenyl)-2-piperidinocyclohexanemethanol recovered ashydrochloride.

EXAMPLE 83 a-(p-Propoxyphenyl)-2-piperidinocyclohexanemethanolhydrochloride In the manner given in Example 32, p-allyloxyphenyl 2-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence ofplatinum oxide to give a-(p-propoxyphenyl)-2-piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 83A Cis-A-a-(p-allyloxyphenyl)-2piperidinocyclohexanemet hanol Amixture of 11.6 g. (0.04 mole) ofcis-A-a-(p-hydroxyphenyl)-2-piperidinocyclohexanemethanol and 1.8 g. ofa 53.3 percent mineral oil dispersion of sodium hydride (0.04 mole ofsodium hydride) in 100 ml. of dimethyl sulfoxide was stirred for aperiod of 1 hour. A solution of 4.9 g. (0.0404 mole) of allyl bromide in15 ml. of ether was added to the mixture above during a period of 15minutes and the obtained reaction mixture was stirred for 3 hours atroom temperature and then poured in l l. of ice water. A white solidseparated which was extracted three times with ether. The ether extractswere combined, washed with water and saturated sodium chloride solution,dried over anhydrous sodium sulfate and evaporated to give a residue.This residue was twice recrystallized from ether-pentane to give a totalof l 1.8 g. (89 percent) ofcis-A-a-(p-allyloxyphenyl)-2-piperidinocyclohexanemethanol of meltingpoint 70-72 C.

Analysis:

Calcd. for C I-I NO Found: 9.10 N, 4.20

The above compound is useful as an oral antidiabetic agent.

EXAMPLE 84a-[p-(Methylcarbamoyloxy)phenyll-2-piperidinocyclohexanemethanolhydrochloride In the manner given in Example 32,p-(methylcarbamoyloxy)-phenyl 2-piperidino-l-cyclohexen-l-yl ketone washydrogenated in the presence of platinum oxide to give a-[p-(methylcarbamoyloxy)-phenyl]-2-piperidinocyclohexanemethanol recoveredas hydrochloride.

EXAMPLE 85 EXAMPLE 86 a-( p-Chlorophenyl )-2-( 2-isopropylpyrrolidino)cyclohexanemethanol hydrochloride In the manner given in Example 32,p-chlorophenyl 2-(2- isopropy1pyrrolidino)-l-cyclohexen-1-yl ketone washydrogenated in the presence of platinum oxide to giveoz-(pchlorophenyl)-2-(2-isopropylpyrrolidino)cyclohexanemet hanolrecovered as hydrochloride.

EXAMPLE 87 a-(p-I-Iydroxyphenyl)-2-octamethyleneiminocyclohexanemethanolhydrochloride In the manner given in Example 32, p-hydroxyphenyl2-0ctamethyleneiminol -cyclohexenl -yl ketone was hydrogenated in thepresence of platinum oxide to givea-(phydroxyphenyl)-2-octamethyleneiminocyclohexanemethanol recovered ashydrochloride.

In the same manner given in Example 32, hydrogenating other ketocompounds of formula II in the presence of platinum oxide gives thesubstituted methanols of the formula IV recovered as hydrochlorides.Representative hydrochlorides, thus obtained, include: thehydrochlorides of a-(o-methylphenyl)-2-pyrrolidinocyclohexanemethanol;a- (p-methylphenyl)-2-pyrrolidinocyclohexanemethanol; a-(2-methoxy-4-methylphenyl)- 2-morpholinocyclohexanemethanol;a-(2-hydroxy-5-chlorophenyl)-2- homomorpholinocyclohexanemethanol;a-[p-(carboxymethoxy)phenyl]-2-(3,6-dimethylhexamethyleneimino)cyclohexanemethanol;a-( 3,4-methylenedioxyphenyl)-2-(Z-methylpiperidino)cyclohexanemethanol;a-(p-ethoxyphenyl)-2-pyrrolidinocycloheptanemethanol; a-( 2,3,4-trimethoxyphenyl )-2-piperidinocyclooctanemethanol; a-( 3 ,5-diiodophenyl)-2-( 3-methylpiperidino)cyclohexanemethanol; a-( 2-methoxy-4- chlorphenyl )-2-piperidinocyclohexanemethanol; a-( 2-methyl-4-trifluoromethylphenyl )-2-piperidinocyclohexanemethanol;a-(3,4-dipropylphenyl)-2-pyrrolidinocyc1oheptanemethanol;a-(2,5-dichlorophenyl)-2-(hexahydro-1H- azepinl -yl)cycloheptanemethanol; a-( 3 ,4-dichlorophenyl)-2 3-methylpiperidino)cyclooctanemethanol; a-(p-propoxyphenyl)-2-(4-butylpiperazino)cyclooctanemethanol; (Jr-(2,5-diiodophenyl)-2-( Z-methylhexaniethylneimino)cyclohepta nemethanol; a-(3-fluorophenyl)-2-pyrrolidinocyclopentanemethanol; a-(2-hexylphenyl)-2-piperidinocyclopentanemethanol; a-( 3-penty1phenyl)-2-piperidinocyclohexanemethanol; a-( Z-butylphenyl)-2-morpholinocyclohexanemethanol; a-( 2-propylphenyl)-2-(l,2,3,4-tetrahydro-lquinolyl)cycloheptanemethanol; a-(3-ethylphenyl)- 2-piperidinocyclooctanemethanol; a-(2-methoxy-5-bromophenyl)-2-pyrrolidinocyclopentanemethanol; a-pheny1-2-octamethyleneim'inocyclooctanemethanol; a-phenyl-Z-(2,3,6-trimethylmorpholino)cycloheptanemethanol; and the like.

EXAMPLE 88 Cis-p-benzyloxyphenyl Z-piperidinocyclohexyl ketone In themanner given in Example 39, p-benzyloxyphenyl 2-piperidino-l-cyclohexen-l-yl ketone dissolved in ethanol washydrogenated in the presence of platinum oxide until one molarequivalent of hydrogen was consumed (42 minutes) to givecis-p-benzyloxyphenyl Z-piperidinocyclohexyl ketone of melting point87.588.5 C.

Analysis:

Calcd. for C H NO C, 79.53; H, 8.28; N, 3.71 Found: C, 78.88; H, 8.27;N, 3.65

In the same manner given in Example 39, selective catalytic reduction(preferably with platinum oxide) of other compounds of formula IIproduces cis-ketones of formula III, e.g., cis-3,4,5-trimethoxyphenyl2-piperidinocyclohexyl ketone; cis-p-ethoxyphenyl Z-piperidinocyclohexylketone; cis-p-(2- hydroxyethoxy)-phenyl 2-piperidinocyclohexyl ketone;cis-ptrifluoromethylphenyl Z-piperidinocyclohexyl ketone;cis-pchlorophenyl 2-(2-isopropylpyrrolidino)cyclohexyl ketone; cis-3,4-methylenedioxyphenyl 2-( hexahydrol I-I-azepinl ketone;cis-2,3,4-trimethoxyphenyl 2- piperidinocyclooctyl ketone; cis-3,4-dichlrophenyl 2-(3- methylpiperidino)cyclooctyl ketone;cis-2,5-dichlorophenyl 2-(hexahydro-1l-I-azepinyl-l-yl)cycloheptylketone; and the like.

In the manner given in Example 41, other cis-alcohols can be obtained byhydrogenating a compound of formula II or III in the presence of acatalyst such as platinum oxide, palladium or the like. Representativecompounds thus obtained include:cis-a-(p-methylphenyl)-2-piperidinocyclohexanemethanol, melting pointl02-l03 C., as hydrochloride melting point 25 l25 3 C.; cis-a-(p-methoxyphenyl )-2-( 4-methyll piperazinyl)cyclohexanemethanol, meltingpoint 132133 C.; cis-a-( p-methoxyphenyl)-2-(4-methylpiperidino)cyclohexanemethanol, melting point 93-94 C.;cis-a-(p-methoxyphenyl)-2-morpholinocyclohexanemethanol, melting point1ll-112 C.; cis-a-(p-methoxyphenyl)-2-( 3-azabicyclo[ 3 ,2,2 ]nonan-3-yl)cyclohexanemethanol, melting point 114.5115.5 C.; cis-a(pmethoxyphenyl)-2-pyrrolidinocyclohexanemethanol, melting point l46-l47C.; cis-a-(p-methoxyphenyl)-2-(2-methylpiperidino)cyclohexanemethanol,as perchlorate, melting point l081 1 1 C.;cisa-(p-methoxyphenyl)-3,3-dimethyl-6- piperidinocyclohexanemethanol,melting point l33l35 C.;cis-a-(4-methoxy-3,S-dimethylphenyl)-2-(hexahydro-1H-azepin-l-yl)cyclohexanemethanol, as hydrochloride, melting point 247248C.; cis a-(2,4-dimethylphenyl)-2-piperidinocyclohexanemethanol, ashydrochloride, melting point 34 239-240 C.; cis-a-( 2,5-dichlorophenyl)-2-heptamethyleneiminocycloheptanemethanol; cis-a-(Z-butylphenyl)-2-morpholinocyclohexanemethanol;cis-a-(Z-propylphenyl)-2-( 1,2,3 ,4-tetrahydro- 1 -quinolyl)cycloheptanemethanol; cisa (2,3,4 trimethoxyphenyl)Z-piperidinocyclooctanemethanol; and the like.

EXAMPLE 89 1-[2-(a,3,4,5-Tetramethoxybenzyl)cyclohexyl]piperidinehydrochloride (isomer cis-A hydrochloride) A solution of 4 g. (0.01mole) of a-(3,4,5-trimethoxyphenyl)-2-piperidinocyclohexanemethanolhydrochloride in 160 ml. of water was basified by adding sufficient 10percent aqueous sodium hydroxide solution. This solution was extractedthree times with 100 ml. of methylene chloride. The methylene chloridesolution was evaporated, leaving an oily free base.

A solution of the free base a-(3,4,5-trimethoxyphenyl)-2-piperidinocyclohexanemethanol in 25 ml. of ether was added to 100 ml. ofliquid ammonia containing 0.01 mole of sodium amide and the mixture wasstirred for a period of 50 minutes, while cooling in Dry Ice-acetone. Asolution of 1.42 g. (0.01 mole) of methyl iodide in 5 ml. of ether wasthen added during 5 minutes; the Dry Ice bath was removed and themixture allowed to stir at room temperature for a period of 7 hours. Itwas then allowed to evaporated overnight (about 20 hours). To thisreaction mixture was then added 50 ml. of water, and the mixture wasextracted with three portions of 50 ml. each of methylene chloride. Thecombined methylene chloride extracts were washed with water, saturatedsalt solution, dried by passing through anhydrous sodium sulfate andevaporated, to give 3.6 g. of an oily product. The oil was dissolved inmethylene chloride and chromatographed on 108 g. of Florisil (anhydrousmagnesium silicate). The column of Florisil was eluted with fourportions, each 200 ml., of a 3 percent acetone-97 percent Skellysolve Bhexanes solution, yielding 1.80 g. of an oil after evaporation of thesolvents. The oil was dissolved in ether and treated with etherealhydrogen chloride to give 1.4 g. of material melting at 227-228 C. Thismaterial was recrystallized from methanol-ether to give 1-[2-(a,3,4,5-tetramethoxybenzyl)cyclohexyl]hpiperidine hydrochloride (isomer cis-Ahydrochloride) of melting point 224-225 C. Ultraviolet: A max. 212(33,400); sh 235 (6,600); 271 (923); sh 279 (646).

Analysis:

calcd. for e igma-H01:

C, 63.82; H, 8.77; CI, 8.56;

Found: C, 63.70; H, 8.95; Cl, 8.25; N

Cis-B-l-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine and hydrochloridethereof A. A solution ofcis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (3.0 g.; 0.01mole) in 50 ml. of methanol was treated with a solution of 5 g. ofhydrogen chloride in 50 ml. of methanol, and an additional 100 ml. ofmethanol was added. The solution was allowed to stand for 18 hours atabout 25 C. and was then evaporated to dryness of 45 C. under reducedpressure. The oily residue was dissolved in 50 ml. of water; thesolution was basified with aqueous sodium hydroxide solution andextracted with ether. The extract was washed with water, then withsaturated sodium chloride solution, dried through anhydrous sodiumsulfate, and evaporated to dryness, to obtain 3.0 g. percent yield) ofcis-B- l 2-( a,p-dimethoxybenzyl)cyclohexyl]piperidine of melting point7577 C. Recrystallization from ethanol gave 2.3 g. of this compound,melting point 8182 C. Ultraviolet: A max. 226 13,200); 275 (1,460); 282(1,210).

Analysis:

Calcd. for C H NO C, 75.67; H, 9.84; N, 4.41 Found: C, 75.70; H, 10.06;N, 4.15

A solution of 10.7 g. (0.0354 mole) ofcis-B-l-[2-(a,pdimethoxybenzyl)cyclohexyl]50 ml. of ether was treatedwith 40 ml. of 1.3 N ethereal hydrogen chloride solution. The resultingsolid was crystallized from 25 ml. of methylene chloride and 50 ml. ofether to give 9.3 g. of cis-B- 1-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine hydrochloride of melting point20921 1 C. Ultraviolet: A max. 227 (12,500); 275 (1,400); 281 (1,200).

Analysis:

Calcd. for C H NO HClZ C, 67.87; H, 9.11;C 1 Found: C, 67.41; H, 9.31; Cl,

B. In the manner given in Example 89, an ether solution ofcis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol was treated inliquid ammonia with sodium amide and methyl iodide. Thecis-B-1-[2-(a,p-dimethoxybenzyl)cyclohexyl1piperidine thus obtained wasidentical with the compound prepared by the above methanolhydrogenchloride etherification procedure.

EXAMPLE 91 Cis-B-l-[2-(a,p-methoxybenzyl)cyclohexyl]piperidine N- oxidehydrate To an lee-cooled solution of 2.2 g. (7 mmoles) of cis-B-1-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine in 50 ml. of methanol wasadded 2.4 g. (14 mmoles) of m-chloroperbenzoic acid. The resultingcolorless solution was allowed to stand in ice for 6 hours and then atroom temperature (23 to 25 C.) for about 18 hours. It was evaporated todryness at 35 C. to give an oily residue. To this residue was added 25ml. of water followed by 25 ml. of percent aqueous sodium hydroxide, andthen the mixture was extracted three times with a total of 100 ml. ofmethylene chloride. The methylene chloride extracts were combined,washed twice with saturated salt solution, dried by passage throughanhydrous sodium sulfate and evaporated to give 2.5 g. of an oil. Theoil was dissolved in 25 ml. of hot ethyl acetate (saturated with water),and the cloudy solution was filtered through a sinter funnel. Theresulting clear solution was evaporated to ml., cooled and seeded. Theresulting crystals were recovered by filtration and washed with ether togive colorless prisms ofcis-B-l-[2-(a,pdimethoxybenzyl)cyclohexyl]melting at l08-1 10 C.

Ultraviolet: A max. 227 (12,750); 275 (1,400); 282 (1,250).

N, 3. C, 68.66; H, 9. N, 3.

99 Found: 96

EXAMPLE 92 Cis-B- l -[2-(a,p-dimethoxybenzyl )cyclohexyl]piperidine andits methiodide A solution of 4 ml. of butyl lithium (0.01 mole) inhexane was added during 2 minutes to a solution of 3.03 g. (0.01 mole)of cis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol in 30 ml.of purified tetrahydrofuran. The mixture was stirred at room temperaturefor 30 minutes and then cooled in a Dry Ice bath at -70 C. To thissolution was added a solution of methyl iodide (1.42 g.; 0.01 mole) in10 ml. of tetrahydrofuran, dropwise, over a period of 10 minutes. Themixture was stirred at 70 C. for a period of 1.5 hours and then at roomtemperature for 19 hours. To the solution was thereupon added water (50ml.) and the solution was then extracted with three portions of 75 ml.each of methylene chloride. The organic extracts were combined, dried bypassage through anhydrous sodium sulfate and evaporated to give 2.7 g.of crude product. The crude product was dissolved in 20 ml. of methylenechloride and chromatographed over 135 g. of neutral alumina. Thematerial was first eluted with eight portions of 250 ml. of a 5 percentether-95 percent Skellysolve B hexanes solution. After evaporation ofthe combined eluates, 1.523 g. of solid material, melting between 82-84C., was obtained. Further elution with two portions of 250 ml. of 25percent ether-75 percent Skellysolve B hexanes, with two portions of 250ml. each of 50 percent ether-50 percent Skellysolve B hexanes and withtwo portions of 250 ml. each of 75 percent ether-25 percent SkellysolveB hexanes gave a total of 0.204 g. of solid material after evaporationof the combined eluates. The above fractions were all combined andrecrystallized from ethanol to give 0.644 g. ofcis-B-l-[2-(a,pdimethoxybenzyl)cyclohexy|]84-85.5 C. This free base wasidentical with the free base obtained in Example 90, parts A and B.

Further elution of the column with 250 ml. of methanol gave 1.446 g. ofmaterial which was crystallized from methanol-ether overnight in therefrigerator to give 0.252 g. of the methiodide ofcis-B-1-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine, melting afteranother recrystallization from methanol-ether at 217218 C.

Ultraviolet: A max. 223 (24,000); 275 (1,390); 281 (1,280).

Analysis:

Calcd. for C H INO C, 54.90; H, 7.46; I, 27.63; Found: C, 55.03; H,7.68; l, 27.63;

EXAMPLE 92A Analysis:

Calcd. for C H ,NO -CH OH-HCl:

C, 65.34; H, 9.40; Cl, 9.19; Found: C, 65.50; H, 9.28; Cl, 8.50;

EXAMPLE 93 Trans-C-l-[2-(a,p-dimethoxybenzyl)cyclohexyl] piperidine Asolution of butyl lithium in hexane (5.25 ml., containing 0.01 mole) wasadded during a period of 10 minutes to a solution ofa-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (3.03 g.; 0.01 moleof the trans-C alcohol) in 40 ml. of tetrahydrofuran in a nitrogenatmosphere. The reaction mixture was then stirred for 45 minutes. It wascooled to C. and thereto was added a solution of 1.41 g. (0.01 mole) ofmethyl iodide in 10 ml. of purified tetrahydrofuran over a period of 30minutes. The mixture was then stirred at room temperature (about 25 C.)overnight for about 16 hours. The reaction mixture was thereuponevaporated to dryness and the resulting residue was dissolved in 50 ml.of water and 50 ml. of methylene chloride. The aqueous layer wasextracted with methylene chloride and the methylene chloride extractscombined, washed with saturated salt solution, dried by passage throughanhydrous sodium sulfate and evaporated, to give 3.2

Analysis:

Calcd. for C d-1 ,190,:

C N, 4.4 l N, 4.7 1

75.67; H, 9.84; Found: C, 75.80;1-1, 10.08;

The same product was obtained. whentrans-C-a-(p-methoxy-phenyl)-2-piperidinocyclohexanemethanol in methanolsolution was treated with anhydrous hydrogen chloride in methanolsolution and the resulting hydrochloride was treated with 20 percentaqueous sodium hydroxide.

, EXAMPLE 94 Trans-D- 1 2-(a,p-dimethoxybenzyl)cyclohexyl1piperidine Ahexane solution of butyl lithium 5.25 ml.; 0.01 mole) was added duringminutes to a solution of trans-D-a-(p-'methoxyphenyl)-2piperidinocyclohexanemethanol (3.03 g.;

0.01 mole) in 30 ml. of purified tetrahydrofuran in a nitrogenatmosphere. The mixture was stirred for a period of 40 minutes, thencooled to 70 C. and a solution of 1.42 (0.01 mole) of methyl iodide in10 ml. of purified tetrahydrofuran was added over a period of 30minutes. The mixture was then stirred for 18 hours at room temperature,evaporated to dryness and the residue dissolved in 50 ml. of water and50 ml. of methylene chloride. The aqueous layer was extracted withmethylene chloride and thecombined methylene chloride extracts werewashed withsaturated salt solution, dried through sodium sulfate andevaporated. The crude product, amounting to 3.2 g., was chromatographedover 100 g. of neutral alumina using five fractions of 150 ml. each of 6percent ether-94 percent Skellysolve B hexanes. The five fractions werecombined and evaporated to give 1.145 g. of oily trans-D-l-[2-(a,p-

dimethoxybenzyl)cyclohexyl]Ultraviolet: A max. 228 (12,-

Analysis:

Calcd. for C H NO C, 75.67; H. 9.84; N, 4.41 Found: C, 75. 8; H, 9.93;N, 4.30

EXAMPLE 95 Trans-C- l 2-( a,p-dimethoxybenzyl)cyclohexyl1piperidine Asolution of 2 g. of hydrogen chloride in ml. of methanol was added to asolution of 0.8 g. (2.64 moles) of a- (p-methoxyphenyl)-2-piperidinocyclohexanemethanol (trans- D isomer) in 40 ml. ofmethanol. The mixture was allowed to stand overnight. The resultingsolution was basified with percent aqueous sodium hydroxide solution.The methanol was evaporated in vacuo, ml. of water was added, and theproduct was extracted with three portions of 25 ml. each of methylenechloride. The extracts were combined, washed with saturated saltsolution, dried over magnesium sulfate and evaporated. The residue (0.08g.) was dissolved in 3 percent ether-97 percent Skellysolve B hexanesand chromatographed over neutral alumina with the same solvent mixture.The column was eluted with ten portionsof ml. each of 3 percent ether-97percent Skellysolve B hexanes and the fractions thus obtained wereevaporated to give 0.351 g. of an oil, which was kept overnight at --l0C. and thereupon solidified. The solidified material was crystallizedfrom methanol to givetrans-C-1-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine of melting point78-79 C., identical with the compound of Example 93.

EXAMPLE 96 1-[ 2-( a-Ethoxy-p-methoxybenzyl)cyclohexyl]piperidine (cis-Aisomer) and the hydrochloride thereof A solution ofcis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (30.3 g.; 0.1mole) in 250 ml. of ether was added during 45 minutes to a suspension offreshly prepared sodium amide (0.2 mole) in l l. of liquid ammonia. Themixture was stirred for 1 hour and then cooled in a Dry Ice-acetonebath. A solution of 31.2 g. (0.2 mole) of ethyl iodide in 100 ml. ofether was added dropwise over a period of 30 minutes, the mixture wasthen stirred'in the cold for 1 hour and allowed to stir without coolingfor 2 hours. The solution was thereupon allowed to evaporate overnight.To the resulting product 500 ml. of water was added, and the mixture wasextracted with 5 portions of 100 ml. each of methylene chloride. Theextracts were combined, washed with water, then with saturated saltsolution, dried by passage through anhydrous sodium sulfate andevaporated to give 30 g. of a yellow oil. A solution of this oil in 200ml. of petroleum ether (boiling range 3060 C.) was allowed tocrystallize overnight to give 15.8 g. (53 percent recovery) of startingalcohol as determined by mixed melting point (78-80 C.). The filtratewas evaporated, and the residue was chromatographed over 750 g. ofneutral alumina. Elution with 6 percent ether-94 percent Skellysolve Bhexanes (8 fractions 250 ml. each) gave 7.23 g. of oilycis-A-1-[2-(a-ethyoxy-p-methoxybenzyl)cyclohexyl]piperidine which was98.9 percent pure as determined by vapor phase chromatography. Furtherelution with 25 percent ether-75 percent Skellysolve B hexanes (4fractions of 250 ml. each) gave 0.546 g. of oil of one component; 50percent ether-50 percent Skellysolve B hexanes (4 fractions 250 ml.each) gave 0.777 g. of oil and 2 fractions of 450 ml. each gave 0.396 g.of oil. Total yield from the ethyl ether fractions were 30 percent. This011 did not crystallize. The oilycis-A-1-[2-(asethoxy-p-methoxybenzyl)cyclohexyl] piperidine had thefollowing analysis: Ultraviolet: A max. 226.5 (12,000); sh 268, 276(1,800); 284 (1,550).

Analysis:

Calcd. for C l-1 190,:

Found The hydrochloride ofcis-A-l-[2-(a-ethoxy-p-methoxybenzyl)-cyclohexyl]piperidine was preparedby treatment of an ethereal solution of the above oily base withethereal hydrogen chloride. Two recrystallizations from ethanol gavecolorless prisms of the hydrochloride of cis-A-l-[2-(a-ethoxy'p-methoxybenzyl)cyclohexy11piperidine of melting point 203-204.5 C.

Ultraviolet: A max. 227 1 1,900); 275 (1,500); 282 (1,300).

Analysis:

Calcd. for C H NO -HCl:

C, 68.55; H, 9.31; Cl, 9.64; Found: C, 68.01; H, 9.42; Cl, 9.72;

EXAMPLE 97 1-[2-(a-Ethoxy-p-methoxybenzyl)cyclohexyllpiperidine (cis-Bisomer)

2. The substituted methanol hydrochloride of claim 1, wherein n is 2,R'', R'''' and R'''''' are 3-, 4-, and 5- methoxy groups, which has amelting point of about 244*-246* C., and is therefore Alpha-(3,4,5-trimethoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanolhydrochloride.
 3. The substituted methanol hydrochloride of claim 1,wherein n is 2, R'' and R'''' are hydrogen, R'''''' is p-methoxy, whichhas a melting point of about 230*-231* C. and is therefore cis-A- Alpha-(p-methoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanolhydrochloride.
 4. The substituted methanol hydrochloride of claim 1,wherein n is 2, R'' and R'''' are hydrogen and R'''''' isp-trifluoromethyl, which has a melting point of about 263*-264* C. andis therefore Alpha-(p-trifluoromethylphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanolhydrochloride.
 5. The substituted methanol hydrochloride of claim 1,wherein n is 2, R, and R'''' are hydrogen, R'''''' is p-chloro, whichhas a melting point of about 274*-275* C. and is therefore Alpha-(p-chlorophenyl)-2-(hexahydro-1H-azepin-1-yl)-cyclohexanemethanolhydrochloride.
 6. The substituted methanol hydrochloride of claim 1,wherein n is 2, R,, R'''', and R'''''' are hydrogen, which has a meltingpoint of about 276*-277* C. and is therefore Alpha-phenyl-2-(hexahydro-1H-azepin-1-yl)cycloHexanemethanol hydrochloride.7. The substituted methanol hydrochloride according to claim 1, whereinn is 2, R, and R'''' are 3- and 4-methoxy and R'''''' is hydrogen, whichhas a melting point of about 225*-226* C. and is therefore Alpha-(3,4-dimethoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanolhydrochloride.
 8. The substituted methanol compound according to claim1, wherein n is 2, R'', and R'''' are hydrogen and R'''''' is p-methoxy,which has a melting point of about 94*-95.5* C. and is therefore cis-B-Alpha (p-methoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanol.9. A substituted methanol quaternary ammonium halide salt according toclaim 1, which is Alpha-(3,4,5-trimethoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanolmethiodide of melting point about 191*-193* C.
 10. The substitutedmethanol hydrochloride compound according to claim 1, wherein n is 2,R'', is 4-methoxy and R'''' and R'''''' are 3-and 4-methyl groups, whichhas a melting point of about 247*-248* C. and is therefore cis- Alpha-(4-methoxy-3,5-dimethylphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanolhydrochloride.